Bleeding Disorders — Platelet and Vessel Wall

Platelet Number and Function Defects

• Thrombocytopenia (<150,000/μL) results from three fundamental mechanisms: (1) decreased production (bone marrow failure, replacement, or suppression), (2) increased destruction (immune-mediated, consumption, sequestration), or (3) dilution (massive transfusion, splenomegaly). Each mechanism produces characteristic bone marrow findings—decreased megakaryocytes in production failure versus normal or increased megakaryocytes in peripheral destruction
• Qualitative platelet disorders involve defects in platelet membrane glycoproteins, granule content, or signaling pathways despite normal platelet numbers. Molecular defects disrupt adhesion (via von Willebrand factor [vWF] and collagen receptors), activation (via thrombin and ADP receptors), aggregation (via fibrinogen cross-linking), or secretion (granule release defects)
• The platelet activation cascade proceeds from vessel injury → exposure of subendothelial collagen and vWF → platelet adhesion via glycoprotein Ib-IX-V and α2β1 → shape change and granule secretion (dense bodies releasing ADP, ATP; alpha granules releasing fibrinogen, vWF) → platelet aggregation through fibrinogen bridges binding to glycoprotein IIb/IIIa → thrombus formation. Defects at any step produce bleeding

Vessel Wall Defects

• The vessel wall provides the structural scaffold for hemostasis through endothelial cell-derived vWF storage and release, subendothelial collagen exposure, and tissue factor delivery. Structural integrity depends on collagen, elastin, and smooth muscle in vessel walls and endothelial cell junctions
• Defects produce impaired adhesion (vWF deficiency/dysfunction), abnormal vascular reactivity (vasculitis), or compromised structural support (hereditary connective tissue disorders, scurvy), all resulting in spontaneous bleeding from small vessels
• Endothelial dysfunction reduces platelet activation and fails to appropriately vasoconstrict, compounding bleeding tendency

Molecular Mechanisms by Disorder Type

• Immune thrombocytopenia (ITP): Autoimmune destruction via IgG antibodies binding platelet surface antigens (particularly glycoprotein IIb/IIIa and Ib-IX-V), leading to complement deposition, phagocytosis by splenic and hepatic macrophages, and shortened platelet survival (hours to days versus normal 7-10 days)
• Thrombotic thrombocytopenic purpura (TTP): Deficiency or inhibition of ADAMTS13 protease, leading to accumulation of ultra-large vWF multimers that spontaneously aggregate platelets in microvasculature without prior vessel injury, causing platelet consumption with characteristic microangiopathic hemolytic anemia
• Henoch-Schönlein purpura (HSP): IgA immune complex deposition in small vessels (skin, GI, kidney, joints) triggers complement activation, vasculitis, and increased vascular permeability
• von Willebrand disease (vWD): Type 1 (quantitative deficiency, 75% of cases), Type 2 (qualitative dysfunction, defective multimer synthesis), or Type 3 (complete absence). Results in defective platelet adhesion due to lack of vWF-collagen bridging and secondary factor VIII deficiency
• Glanzmann thrombasthenia: Loss-of-function mutations in ITGA2B or ITGB3 genes encoding platelet glycoprotein IIb/IIIa, the fibrinogen receptor essential for platelet aggregation, resulting in absence of platelet clumping despite normal adhesion
• Bernard-Soulier syndrome: Mutations affecting GP1BA, GP1BB, or GP9 genes encoding the glycoprotein Ib-IX-V complex, the primary vWF receptor, causing defective adhesion and characteristic giant platelets (macrothrombocytopenia)
• Hereditary connective tissue disorders (Ehlers-Danlos, osteogenesis imperfecta, Marfan syndrome): Mutations in collagen synthesis or assembly genes lead to defective subendothelial collagen and compromised vessel wall structural integrity

Causes of Thrombocytopenia (Decreased Platelet Production)

• Bone marrow disorders: Aplastic anemia, myelodysplastic syndrome, leukemia/lymphoma infiltration, tuberculosis, fungal infections
• Medications: Chemotherapy, certain anticonvulsants, sulfonamides
• Nutritional deficiency: Vitamin B12, folate (impaired megakaryopoiesis)
• Radiation exposure: Cytotoxic effect on hematopoietic stem cells

Causes of Thrombocytopenia (Increased Platelet Destruction)

• Immune: Immune thrombocytopenia (ITP)—both acute (post-viral, post-vaccination) and chronic forms
• Thrombotic microangiopathy: Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), prosthetic valves
• Medications: Heparin (heparin-induced thrombocytopenia [HIT]), quinine, sulfonamides, NSAIDs
• Infections: HIV, CMV, sepsis, dengue
• Autoimmune: Systemic lupus erythematosus (SLE), antiphospholipid syndrome
• Post-transfusion: Alloimmunization to HPA or HLA antigens

Causes of Thrombocytopenia (Sequestration/Dilution)

• Splenic sequestration: Splenomegaly from cirrhosis, portal hypertension, lymphoproliferative disorders
• Massive transfusion/dilution: >15 units packed RBCs without platelet replacement

Qualitative Platelet Disorders (Normal/High Count)

• Inherited: Glanzmann thrombasthenia, Bernard-Soulier syndrome, storage pool disease (alpha, delta, gray platelet), cyclooxygenase deficiency
• Acquired: Medications (aspirin, NSAIDs, clopidogrel, ticlopidine), uremia, liver disease, anticoagulation, sepsis

von Willebrand Disease

• Type 1 (75%): Quantitative deficiency
• Type 2 (20%): Qualitative dysfunction (multiple subtypes with variable severity)
• Type 3 (5%): Complete deficiency

Vessel Wall Disorders

• Vasculitis: Henoch-Schönlein purpura (IgA-mediated small vessel vasculitis), polyarteritis nodosa, granulomatosis with polyangiitis, microscopic polyangiitis
• Hereditary connective tissue disorders: Ehlers-Danlos syndrome (Type IV most severe for bleeding), osteogenesis imperfecta, Marfan syndrome
• Scurvy: Vitamin C deficiency impairing collagen cross-linking
• Telangiectasia: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
• Acquired: Medications (corticosteroids causing skin fragility), amyloidosis, senile purpura

Characteristic Mucocutaneous Bleeding Pattern

Cardinal Bleeding Symptoms

• Petechiae: Small (<2-3 mm) non-blanching red-purple macules appearing in crops, characteristically on lower extremities and areas of pressure; indicate severe thrombocytopenia (<20,000/μL when spontaneous) or platelet dysfunction with defective adhesion
• Purpura: Larger (>3 mm) hemorrhagic lesions; may be palpable in vasculitis (raised, tender) versus non-palpable in ITP (flat)
• Ecchymoses (bruising): Larger confluent areas of bleeding, particularly on lower extremities; development with minimal trauma or spontaneous suggests platelet dysfunction or severe thrombocytopenia
• Epistaxis: Recurrent or prolonged nosebleeds from mucosal capillary bleeding; particularly common in vWD and HSP
• Mucosal bleeding: Gum bleeding (especially with poor dental hygiene), oral ulceration, blood-filled blisters (bullae hemorrhagica); severity correlates with platelet count
• GI bleeding: Melena or hematochezia from mucosal ulceration and erosion; acute GI hemorrhage can precipitate hemodynamic instability
• Menorrhagia: Heavy or prolonged menses (>7 days, soaking >1 pad/hour) in women; most common bleeding manifestation of vWD and mild thrombocytopenia
• Hematuria: Usually microscopic but can be gross; suggests lower GI or GU mucosal bleeding

Physical Examination Findings

• Petechial rash pattern: Non-blanching, widespread distribution especially on lower extremities, buttocks, and areas of pressure; in HSP, often palpable with raised, tender appearance (distinguish from ITP)
• Splenomegaly: Enlarged spleen on palpation (>2 cm below costal margin); indicates chronic immune destruction (chronic ITP) or sequestration (portal hypertension, splenic infiltration)
• Hepatomegaly: Suggests systemic disease (cirrhosis with sequestration, lymphoproliferative disorder, infection like CMV)
• Mucous membrane involvement: Bleeding gums, petechiae on hard/soft palate, oral ulceration
• Skin fragility and poor wound healing: Ehlers-Danlos and scurvy (also note perifollicular hemorrhages, corkscrew hairs in scurvy)
• Telangiectasias: Visible small dilated vessels on lips, mucous membranes, fingers (hereditary hemorrhagic telangiectasia)
• Arthralgia/arthritis: Particularly knees and ankles in HSP; non-permanent deformity

Laboratory Correlates

• Platelet count: Correlates with bleeding risk and location; <20,000/μL → spontaneous bleeding (CNS, GI); 20,000-50,000/μL → bleeding with minor trauma; >50,000/μL → bleeding with major trauma only; >100,000/μL → typically hemostatic unless qualitative defect
• Bleeding time (rarely used now): Prolonged in platelet dysfunction but unreliable; normal or prolonged PT and aPTT (absent coagulation factor deficiency)
• Peripheral blood smear: Shows platelet number and morphology; giant platelets in Bernard-Soulier and inherited macrothrombocytopenias; schistocytes (fragmented RBCs) in TTP/HUS; absent platelets in Glanzmann thrombasthenia
• Reticulocytosis with microangiopathic hemolytic anemia: TTP/HUS with spherocytes, schistocytes and elevated LDH, bilirubin, low haptoglobin
• Coagulation studies: Prolonged aPTT in Type 3 vWD (secondary Factor VIII deficiency); normal in Type 1 vWD and most platelet disorders

Organ-Specific Manifestations

• CNS bleeding (ICH, subdural hematoma): Life-threatening complication in severe thrombocytopenia (<10,000/μL) or severe qualitative defects; presents with altered mental status, focal neurologic deficits, headache
• Renal involvement: Microscopic hematuria universal in HSP; can progress to crescentic glomerulonephritis with acute kidney injury
• GI involvement: HSP causes abdominal pain, melena, bloody diarrhea; intussusception risk in children; can present as acute abdomen mimicking appendicitis

Initial Laboratory Assessment

• Complete blood count (CBC): Essential first test; platelet count classifies as thrombocytopenia versus normal; MCV helps identify nutritional deficiency; WBC and RBC indices suggest bone marrow process
• Peripheral blood smear: Morphologic assessment of platelet size, number, and granulation; identifies schistocytes (TTP/HUS), anisopoikilocytosis (dysplasia), hypersegmented neutrophils (B12/folate deficiency); platelet morphology is key diagnostic clue
• Reticulocyte count and LDH: If hemolysis suspected (TTP/HUS); elevated LDH and reticulocytosis indicate hemolytic anemia
• Coagulation panel (PT, aPTT, fibrinogen): Should be normal in isolated platelet/vessel disorders (distinguishes from coagulation factor deficiency or DIC); prolonged aPTT suggests secondary Factor VIII deficiency in severe vWD or associated coagulation disorder

Platelet Function Testing (When Count Normal or Mildly Reduced with Bleeding)

• Platelet aggregometry: Gold standard for qualitative platelet disorders; measures platelet clumping in response to agonists (ADP, epinephrine, collagen, arachidonic acid, ristocetin); absent aggregation to all agonists = Glanzmann thrombasthenia; absent or reduced aggregation to ristocetin = Bernard-Soulier or vWD; abnormal aggregation pattern = storage pool disease (biphasic response absent)
• Flow cytometry: Identifies absent or severely reduced glycoprotein expression; absent GpIIb/IIIa (Glanzmann); absent GpIb (Bernard-Soulier)
• Platelet electron microscopy: Visualizes absent dense granules (delta storage pool disease) or abnormal alpha granules

von Willebrand Disease Diagnosis

• von Willebrand factor (vWF:Ag): Antigen level; reduced in Type 1 and Type 3 vWD
• von Willebrand factor activity (vWF:RCo or vWF:GPM): Ristocetin cofactor activity or glycoprotein M binding; disproportionately reduced in Type 2 vWD (abnormal multimer assembly)
• Factor VIII activity: Often reduced in vWD (especially Type 3); normal or near-normal in most qualitative platelet disorders
• vWF:RCo/vWF:Ag ratio: <0.6 suggests Type 2 vWD (dysfunction); >0.6 in Type 1
• vWF multimer analysis (specialized test): Type 1 = all multimers present but reduced; Type 2 = abnormal pattern (missing intermediate/large multimers); Type 3 = absence of all multimers
• Diagnosis challenging: vWF is acute phase reactant (rises with stress, inflammation, estrogen, pregnancy); may require repeat testing; Type

Immediate stabilisation

• Life-threatening hemorrhage (ICH, massive GI bleed): airway/hemodynamic support, hold antiplatelet and anticoagulant drugs, and give platelet transfusion plus IVIG and IV methylprednisolone in immune thrombocytopenia (ITP) — this is the one setting in which platelets are transfused in ITP despite rapid antibody-mediated clearance. Antifibrinolytics (tranexamic acid) help mucosal bleeding by blocking plasminogen binding to fibrin.

Disease-specific first-line therapy

• ITP: per the ASH 2019 ITP guideline, adults with platelets ≥30,000/μL and no bleeding are observed; below that, corticosteroids (prednisone or dexamethasone) blunt macrophage Fc-receptor–mediated clearance and antibody production. IVIG is added when a rise is needed within 24–48 h (Fc-receptor blockade of splenic macrophages). Most children are observed regardless of count if bleeding is absent.
• TTP: a medical emergency — per ISTH 2020 guidance, start therapeutic plasma exchange urgently (replaces ADAMTS13, removes inhibitor and ultra-large multimers) with corticosteroids and the anti-vWF nanobody caplacizumab; rituximab for immune TTP. Do not delay for ADAMTS13 results.
• HIT: stop all heparin and start a non-heparin anticoagulant (argatroban, fondaparinux, or a DOAC) per the ASH 2018 VTE/HIT guideline; warfarin alone early risks venous limb gangrene.
• von Willebrand disease: per the ASH/ISTH/NHF/WFH 2021 vWD guidelines, desmopressin (DDAVP) releases endothelial Weibel-Palade vWF in responsive type 1 disease; vWF-containing factor concentrate for type 3, type 2, or major surgery; tranexamic acid and hormonal therapy for menorrhagia.
• Inherited platelet function defects (Glanzmann, Bernard-Soulier): antifibrinolytics and local measures first; HLA-matched platelet transfusion or recombinant factor VIIa for severe bleeding.
• Uremic platelet dysfunction: dialysis, DDAVP, cryoprecipitate, correction of anemia.
• IgA vasculitis (HSP): supportive care; glucocorticoids for severe GI or renal disease, with RAS blockade for persistent proteinuria (KDIGO 2021 glomerular disease guideline).

Escalation and definitive therapy

• Second-line ITP: TPO receptor agonists (eltrombopag, romiplostim), rituximab, or splenectomy (removes the main site of antibody production and platelet destruction); vaccinate against encapsulated organisms beforehand.

Contraindicated

• Platelet transfusion in TTP or HIT unless there is life-threatening bleeding — it fuels microvascular thrombosis.
• DDAVP in type 2B vWD (worsens thrombocytopenia) and in young children/those unable to fluid-restrict.
• Aspirin, NSAIDs, and IM injections in any platelet disorder.

Complications of disease (emergencies flagged)

• Intracranial hemorrhage — emergency: the feared complication of severe thrombocytopenia or severe qualitative defects; signals itself as new headache, vomiting, focal deficit, or altered mental status. Requires immediate platelet transfusion, IVIG plus steroids in ITP, and emergent neuroimaging.
• Microvascular thrombosis in TTP — emergency: ultra-large vWF multimers occlude arterioles in brain, heart, and kidney; signalled by fluctuating neurologic deficits, rising troponin, or AKI with schistocytes and very high LDH.
• Thrombosis in HIT (HITT) — emergency: PF4–heparin immune complexes cross-link platelet FcγRIIa causing platelet activation; the signal is a >50% platelet fall 5–10 days after heparin exposure with new venous or arterial thrombosis, not bleeding.
• Intussusception and GI hemorrhage in IgA vasculitis — emergency in children: bowel-wall edema from IgA immune-complex vasculitis forms a lead point; suspect with colicky abdominal pain and currant-jelly stool.
• Crescentic glomerulonephritis and CKD: mesangial IgA deposition; heralded by rising proteinuria, hypertension, and RBC casts — the main determinant of long-term prognosis.
• Iron deficiency anemia: chronic menorrhagia or occult GI loss in vWD and telangiectasia syndromes.

Complications of treatment

• Corticosteroids: hyperglycemia, hypertension, osteoporosis, adrenal suppression, and infection; avoid prolonged courses.
• IVIG: aseptic meningitis, volume overload, acute kidney injury (sucrose-containing products), and thrombosis; hemolysis from anti-A/anti-B isoagglutinins.
• Rituximab: hypogammaglobulinemia, hepatitis B reactivation (screen HBsAg/anti-HBc before use), and rare progressive multifocal leukoencephalopathy.
• Splenectomy: lifelong risk of overwhelming post-splenectomy infection from encapsulated organisms — emergency; prevent with pneumococcal, meningococcal, and Hib vaccination before surgery per CDC/ACIP schedules.
• TPO receptor agonists: thrombosis, rebound thrombocytopenia on withdrawal, and hepatotoxicity with eltrombopag.
• DDAVP: free-water retention causing hyponatremia and seizures — fluid-restrict; tachyphylaxis after repeated doses; worsens thrombocytopenia in type 2B vWD.
• Caplacizumab: mucocutaneous bleeding from functional vWF blockade.
• Plasma exchange: citrate-induced hypocalcemia (perioral tingling, QT prolongation), catheter thrombosis and infection.
• Tranexamic acid: avoid with upper-tract hematuria (clot retention and ureteral obstruction).
• Repeated platelet transfusion in Glanzmann thrombasthenia: anti-GPIIb/IIIa alloimmunization causing refractoriness.

• Mucocutaneous vs. deep bleeding is the first fork: petechiae, epistaxis, gum bleeding, and menorrhagia point to platelets/vessel wall; hemarthrosis and delayed deep muscle bleeding point to a factor deficiency (hemophilia).
• **Giant platelets + thrombocytopenia + absent ristocetin aggregation = *Bernard-Soulier* (GPIb-IX-V, the vWF receptor). The distinguishing step: adding normal plasma corrects the ristocetin defect in vWD but not** in Bernard-Soulier, because the missing element in BSS is the receptor, not the ligand.
• **Normal ristocetin aggregation with absent aggregation to ADP, collagen, and epinephrine = *Glanzmann thrombasthenia* (GPIIb/IIIa); the smear shows isolated platelets with no clumping** and a normal count.
• Do not transfuse platelets in TTP or HIT — the single most tested management distractor. In TTP the best next step is urgent plasma exchange, started before ADAMTS13 activity returns; MAHA plus thrombocytopenia without another cause is enough, and the classic pentad is usually incomplete.
• **Palpable purpura on buttocks and lower legs with arthralgia, abdominal pain, and hematuria in a child after a URI = *IgA vasculitis (Henoch-Schönlein purpura)* — and the platelet count is normal**. Choosing ITP here is the classic trap; ITP purpura is flat and non-palpable.
• vWD is the most common inherited bleeding disorder; expect normal platelet count, prolonged aPTT only when factor VIII is low, and a family history of menorrhagia. DDAVP is contraindicated in type 2B, where it precipitates thrombocytopenia by clearing hyperadhesive vWF-platelet complexes.
• Platelet count fall of >50% on days 5–10 of heparin with new clot, not bleeding, = HIT: stop heparin and start argatroban or fondaparinux; do not simply switch to LMWH and do not start warfarin alone.
• **Perifollicular hemorrhage, corkscrew hairs, and bleeding gums with a normal platelet count and normal PT/aPTT = *scurvy*** — defective collagen hydroxylation, treated with vitamin C.
• Bleeding time is obsolete: never the best next test. Choose CBC with peripheral smear first, then targeted vWF panel or platelet aggregometry.