Bleeding Disorders

Bleeding disorders span defects of vessels, platelets, and coagulation factors. The single most exam-relevant skill is using the PT / APTT pattern to localise the lesion, then layering in haemophilia, von Willebrand disease (vWD), immune thrombocytopenia (ITP), and disseminated intravascular coagulation (DIC). Master the screening tests and you have answered most of the question stems.

The haemostatic system — a quick framework

Haemostasis happens in two overlapping phases:

1. Primary haemostasis → platelet plug formation. Depends on the vessel wall, platelets, and von Willebrand factor (vWF). Defects cause mucocutaneous bleeding — petechiae, purpura, epistaxis, menorrhagia, gum bleeding, bleeding immediately after trauma/surgery.
2. Secondary haemostasis → the coagulation cascade generates fibrin to stabilise the plug. Depends on clotting factors. Defects cause deep bleeding — haemarthrosis, muscle haematoma, retroperitoneal bleeds, and delayed re-bleeding hours after trauma.

High-yield: Mucocutaneous + petechiae = platelet/vWF problem (primary). Haemarthrosis + deep muscle bleeds = coagulation factor problem (secondary). This single dichotomy decides the differential before any test.

Classification of bleeding disorders

Category	Mechanism	Prototype disorders
Vascular	Vessel wall fragility	Henoch–Schönlein purpura, scurvy, hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu), senile purpura
Platelet — quantitative	Thrombocytopenia	ITP, TTP, DIC, marrow failure, hypersplenism
Platelet — qualitative	Dysfunction	Glanzmann thrombasthenia (GpIIb/IIIa), Bernard–Soulier (GpIb), aspirin, uraemia
vWF	Adhesion defect	von Willebrand disease
Coagulation — inherited	Single factor deficiency	Haemophilia A (VIII), B (IX), C (XI)
Coagulation — acquired	Multiple factors	DIC, liver disease, vitamin K deficiency, warfarin

Localising the defect with PT and APTT

This is the backbone of the topic.

• PT (prothrombin time) → extrinsic + common pathway = factors VII, X, V, II (prothrombin), I (fibrinogen). Reported as INR. Most sensitive to factor VII (shortest half-life → first to fall in liver disease/warfarin).
• APTT (activated partial thromboplastin time) → intrinsic + common pathway = factors XII, XI, IX, VIII plus common factors.
• Thrombin time (TT) → final step, fibrinogen → fibrin. Prolonged in heparin, hypo/dysfibrinogenaemia, DIC.

Approach: isolated prolonged PT → extrinsic (VII) → think early liver disease, early warfarin, factor VII deficiency. Isolated prolonged APTT → intrinsic → think haemophilia A/B, vWD, lupus anticoagulant, heparin. Both prolonged → common pathway or global defect → DIC, liver disease, vitamin K deficiency, warfarin overdose.

Pattern	PT	APTT	Likely cause
↑ PT only	↑	N	Factor VII deficiency, early liver disease, early warfarin
↑ APTT only	N	↑	Haemophilia A/B, vWD, factor XI/XII, heparin, lupus anticoagulant
↑ PT + ↑ APTT	↑	↑	DIC, liver disease, vitamin K deficiency, warfarin, factor X/V/II/I deficiency
Both normal but bleeding	N	N	Platelet disorder, vWD (mild), factor XIII deficiency, vascular cause

High-yield: Factor XII deficiency prolongs APTT but does NOT cause bleeding (it may even cause thrombosis). A classic "prolonged APTT, no bleeding" stem.

High-yield: Factor XIII deficiency has normal PT, APTT, and platelet count — diagnosed by urea clot solubility test. Presents with delayed bleeding, poor wound healing, and umbilical stump bleeding in neonates.

Mixing study (50:50)

When APTT (or PT) is prolonged, mix patient plasma with normal plasma 1:1:

• Corrects → factor deficiency (the normal plasma supplies the missing factor).
• Fails to correct → inhibitor present (e.g., factor VIII inhibitor, lupus anticoagulant).

Haemophilia A and B

Both are X-linked recessive → affect males; females are carriers (occasionally symptomatic via lyonisation). About 30% are new mutations (no family history).

• Haemophilia A = factor VIII deficiency (most common, ~80–85%).
• Haemophilia B (Christmas disease) = factor IX deficiency.
• Haemophilia C = factor XI deficiency — autosomal, common in Ashkenazi Jews, milder.

Clinical features: haemarthrosis (knee > elbow > ankle — leading to target joints and chronic arthropathy), deep muscle haematomas (iliopsoas → can mimic appendicitis, causes femoral nerve palsy), prolonged bleeding after surgery/dental extraction, intracranial haemorrhage. No petechiae (primary haemostasis intact).

Severity by factor level:

Severity	Factor level	Bleeding
Severe	< 1%	Spontaneous bleeds, haemarthrosis
Moderate	1–5%	Bleed after minor trauma
Mild	5–40%	Bleed only after surgery/major trauma

Labs: prolonged APTT, normal PT, normal platelets, normal bleeding time. Specific factor assay confirms and distinguishes A from B. Mixing study corrects (unless inhibitor present).

Management — drug of choice:

• Severe / acute bleed: factor replacement — recombinant factor VIII (haemophilia A) or factor IX (haemophilia B). 1 IU/kg of VIII raises level ~2%; of IX raises ~1%.
• Mild haemophilia A only: DDAVP (desmopressin) — releases stored vWF–VIII from endothelium. Useless in haemophilia B and in severe A.
• Adjuncts: antifibrinolytics (tranexamic acid, ε-aminocaproic acid) for mucosal/dental bleeds.
• Inhibitor (alloantibody) development: the major complication of replacement; treat with bypassing agents — recombinant factor VIIa or activated prothrombin complex concentrate (FEIBA). Emicizumab (bispecific antibody bridging IXa and X) is now a standard prophylaxis, especially with inhibitors.
• Gene therapy (AAV-delivered) is an emerging cure-intent therapy.

High-yield: DDAVP works in mild haemophilia A and type 1 vWD, but is contraindicated in type 2B vWD (causes thrombocytopenia) and is ineffective in haemophilia B.

High-yield: Avoid IM injections, aspirin, and NSAIDs in haemophiliacs. Use paracetamol for analgesia.

Mnemonic: "All 8 = haemophilia A is factor VIII" (and B = IX, "Be9").

Von Willebrand disease (vWD)

Most common inherited bleeding disorder (autosomal dominant, mostly). vWF has two jobs: (1) mediates platelet adhesion (binds GpIb to subendothelium), and (2) acts as carrier for factor VIII, protecting it from degradation. Hence vWD causes a mixed picture — mucocutaneous bleeding (primary) plus a secondary rise in APTT when VIII falls.

Types:

Type	Defect	Notes
1 (~75%)	Partial quantitative ↓	Mildest, most common; responds to DDAVP
2	Qualitative defect	Subtypes 2A, 2B, 2M, 2N
2B	↑ affinity for GpIb	Causes thrombocytopenia; DDAVP contraindicated
2N	↓ VIII binding	Mimics haemophilia A
3	Near-complete deficiency	Severe, autosomal recessive; needs vWF concentrate

Clinical features: epistaxis, easy bruising, menorrhagia (common presentation in young women), bleeding after dental/surgical procedures, GI bleeding (angiodysplasia association).

Labs: prolonged bleeding time / PFA-100 closure time, normal/↑ PT, APTT may be prolonged (low VIII), normal platelet count (except type 2B). Confirmatory tests:

• vWF antigen (quantity)
• Ristocetin cofactor activity (function — the key functional test)
• Factor VIII level
• RIPA (ristocetin-induced platelet aggregation): decreased in most vWD; increased sensitivity (aggregation at low ristocetin) in type 2B and platelet-type pseudo-vWD.

High-yield: Ristocetin cofactor activity is the functional assay for vWF. Ristocetin causes vWF to bind GpIb → platelet agglutination. In Bernard–Soulier (GpIb defect), RIPA also fails and does not correct with normal plasma (platelet defect, not plasma factor).

Management:

• Type 1: DDAVP (drug of choice).
• Types 2 (most) and 3: vWF-containing factor VIII concentrate (e.g., Humate-P).
• Antifibrinolytics and tranexamic acid for menorrhagia; combined OCPs help menorrhagia.

Immune (idiopathic) thrombocytopenic purpura — ITP

An autoimmune disorder: anti-platelet antibodies (anti-GpIIb/IIIa, anti-GpIb) opsonise platelets → destroyed by splenic macrophages. It is a diagnosis of exclusion (isolated thrombocytopenia with otherwise normal counts and smear).

Feature	Acute ITP	Chronic ITP
Typical age	Children (2–6 yr)	Adults, women
Trigger	Post-viral	Often none / autoimmune
Onset	Abrupt	Insidious
Course	Self-limited (weeks)	Persistent > 12 months
Treatment	Often observation	Usually needs therapy

Clinical features: petechiae, purpura, mucosal "wet purpura" (oral blood blisters → higher bleed risk), epistaxis, menorrhagia. Splenomegaly is absent (its presence should prompt another diagnosis). Serious intracranial bleeding is rare.

Labs: isolated thrombocytopenia; normal Hb and WBC; peripheral smear shows large platelets (megathrombocytes), no schistocytes; PT and APTT normal. Bone marrow (if done, e.g., atypical/older patient) shows normal or increased megakaryocytes. Antiplatelet antibody testing is not routinely required.

Management flow: Platelets > 30,000 and no bleeding → observe. Bleeding or platelets < 30,000 → first-line corticosteroids (prednisolone) or IVIG / anti-D (faster, used when rapid rise needed e.g. active bleed, pre-procedure). Refractory/relapsing → thrombopoietin receptor agonists (eltrombopag, romiplostim), rituximab, or splenectomy. Life-threatening bleed → IVIG + high-dose steroids + platelet transfusion.

High-yield: IVIG and anti-D raise the platelet count fastest (use before surgery or in active bleeding). Steroids are first-line maintenance. TPO agonists (eltrombopag, romiplostim) are key second-line agents — frequently tested newer drugs.

High-yield: Platelet transfusion alone in ITP is largely consumed by antibodies — reserve for life-threatening haemorrhage, given alongside IVIG/steroids.

Disseminated intravascular coagulation — DIC

A consumption coagulopathy: widespread activation of coagulation (usually by tissue factor) → microvascular fibrin thrombi → consumption of platelets and clotting factors → simultaneous thrombosis and bleeding. Fibrinolysis is activated, generating D-dimer/FDPs.

Causes (mnemonic "STOP Making New Thrombi"): Sepsis (gram-negative — commonest), Trauma, Obstetric (abruptio placentae, amniotic fluid embolism, retained dead fetus, HELLP), Pancreatitis, Malignancy (acute promyelocytic leukaemia, M3 — classic), Neoplasm/mucin-secreting adenocarcinoma, Transfusion reaction, snake bite.

Labs (the classic combination):

Test	Result in DIC
Platelets	↓ (low)
PT	↑ (prolonged)
APTT	↑ (prolonged)
Fibrinogen	↓ (low)
D-dimer / FDPs	↑↑ (high)
Peripheral smear	Schistocytes (MAHA)

High-yield: DIC = everything abnormal — low platelets, prolonged PT and APTT, low fibrinogen, high D-dimer, schistocytes. D-dimer is the most sensitive; falling fibrinogen is a useful marker of severity.

Management: treat the underlying cause (the cornerstone). Supportive: FFP (replaces factors + fibrinogen), cryoprecipitate (if fibrinogen very low, < 100 mg/dL), platelet transfusion if bleeding. In APML/M3, ATRA (all-trans retinoic acid) treats the leukaemia and the DIC. Heparin is reserved for predominantly thrombotic DIC (e.g., purpura fulminans).

Vitamin K deficiency and liver disease

• Vitamin K is needed for γ-carboxylation of factors II, VII, IX, X and proteins C & S. Deficiency → ↑ PT first (VII shortest half-life), then APTT. Causes: malabsorption, prolonged antibiotics, newborn (haemorrhagic disease of newborn — prevented by IM vitamin K at birth), warfarin.
• Liver disease: all factors fall except factor VIII (made by endothelium, often normal/high). So VIII normal/high + low V suggests liver disease rather than DIC, where both V and VIII fall.

High-yield: Factor VIII distinguishes liver disease (normal/high VIII) from DIC (low VIII). Factor V is low in both.

Key differentials

Disorder	Platelets	PT	APTT	BT	Distinguishing test
Haemophilia A/B	N	N	↑	N	Factor VIII / IX assay
vWD	N (↓ in 2B)	N	N/↑	↑	Ristocetin cofactor, vWF Ag
ITP	↓	N	N	↑	Diagnosis of exclusion
DIC	↓	↑	↑	↑	↓ fibrinogen, ↑ D-dimer, schistocytes
TTP	↓	N	N	↑	↓ ADAMTS13, schistocytes, pentad
Glanzmann	N	N	N	↑	Absent aggregation to all agonists except ristocetin
Bernard–Soulier	↓ (large)	N	N	↑	No agglutination to ristocetin
Vitamin K def	N	↑	↑ (later)	N	Corrects with vitamin K

TTP vs DIC vs ITP: TTP gives a pentad — MAHA (schistocytes), thrombocytopenia, fever, renal dysfunction, neurological signs — with normal PT/APTT (unlike DIC) due to ADAMTS13 deficiency (ultralarge vWF multimers). Treatment is plasma exchange (NOT platelet transfusion — contraindicated, worsens thrombosis). ITP has isolated thrombocytopenia with no schistocytes and normal coagulation.

Glanzmann vs Bernard–Soulier:

• Glanzmann thrombasthenia: GpIIb/IIIa defect (fibrinogen receptor → aggregation fails). Aggregation absent to ADP, collagen, epinephrine but normal to ristocetin. Platelet count and size normal.
• Bernard–Soulier syndrome: GpIb defect (vWF receptor → adhesion fails). Large platelets, thrombocytopenia, no agglutination with ristocetin.

Recently asked / exam angle

• PT/APTT localisation tables are the single most repeated theme — given a pattern, name the disorder.
• Factor XII prolongs APTT but no bleeding; factor XIII normal screen + urea clot solubility test; factor VII most sensitive marker of early liver disease/warfarin.
• DDAVP indications/contraindications — works in mild haemophilia A and type 1 vWD; contraindicated in type 2B vWD; useless in haemophilia B.
• Ristocetin physiology — distinguishes vWD from Bernard–Soulier (mixing study corrects vWD, not BSS).
• ITP newer drugs — eltrombopag, romiplostim (TPO agonists), rituximab; IVIG/anti-D fastest to raise count.
• DIC labs as a complete panel and APML → ATRA; factor VIII to separate DIC from liver disease.
• TTP pentad + ADAMTS13 + plasma exchange, and that platelet transfusion is contraindicated in TTP.
• Image/smear stems: schistocytes (DIC/TTP), large platelets (ITP, BSS).

Rapid revision

1. Mucocutaneous + petechiae = primary (platelet/vWF); haemarthrosis + deep bleed = secondary (factor).
2. PT = extrinsic (VII) + common; APTT = intrinsic (XII, XI, IX, VIII) + common.
3. Haemophilia A = VIII, B (Christmas) = IX, both X-linked; prolonged APTT, normal PT.
4. DDAVP: mild haemophilia A + type 1 vWD; contraindicated in type 2B, useless in haemophilia B.
5. vWF does two jobs — platelet adhesion (GpIb) and factor VIII carrier; ristocetin cofactor is the functional test.
6. Factor XII deficiency → long APTT, no bleeding (may thrombose).
7. Factor XIII deficiency → normal screening tests, diagnosed by urea clot solubility, neonatal umbilical bleeding.
8. ITP = isolated thrombocytopenia, large platelets, no splenomegaly; IVIG/anti-D fastest, steroids first-line, TPO agonists second-line.
9. DIC = ↓ platelets, ↑ PT, ↑ APTT, ↓ fibrinogen, ↑↑ D-dimer, schistocytes; treat the cause; APML → ATRA.
10. Liver disease vs DIC: factor VIII normal/high in liver disease, low in DIC.
11. TTP pentad + ↓ ADAMTS13 → plasma exchange; platelet transfusion contraindicated.
12. Mixing study corrects → deficiency; fails to correct → inhibitor (factor VIII inhibitor, lupus anticoagulant).