Bleeding & Platelet Disorders

Localizing the Defect: Primary vs Secondary Hemostasis

Two stages. In primary hemostasis, platelets adhere to subendothelial collagen through von Willebrand factor (vWF) bound to platelet GpIb, then aggregate as fibrinogen bridges GpIIb/IIIa receptors. In secondary hemostasis, the coagulation cascade builds a fibrin mesh that stabilizes the plug.

Primary (platelet or vessel) defects. Bleeding is immediate and superficial: petechiae, mucocutaneous bleeding, epistaxis, gum bleeding, and menorrhagia, with a prolonged bleeding time.

Secondary (coagulation factor) defects. Bleeding is deep: hemarthroses, muscle hematomas, and delayed rebleeding once the unsupported platelet plug gives way, with a prolonged PT or PTT.

Reading the labs. The platelet count measures quantity and the bleeding time measures function. The PT tests the extrinsic and common pathways (VII, X, V, II, fibrinogen); the PTT tests the intrinsic and common pathways (XII, XI, IX, VIII, then the common factors). A mixing study with normal plasma corrects a factor deficiency but not an inhibitor.

Thrombocytopenia: Destruction and Consumption

Immune thrombocytopenia (ITP). IgG autoantibodies against platelet GpIIb/IIIa lead to splenic destruction. The result is an isolated low platelet count with normal PT/PTT and INCREASED marrow megakaryocytes compensating for peripheral destruction. Children develop an acute post-viral form that usually resolves; adults develop a chronic form, sometimes secondary to SLE, HIV, or CLL. Maternal IgG can cross the placenta and cause transient neonatal thrombocytopenia. Treat with corticosteroids and IVIG, then splenectomy for refractory disease.

Thrombotic thrombocytopenic purpura (TTP). ADAMTS13 normally cleaves large vWF multimers. When it is deficient or inhibited (usually by an acquired autoantibody), the multimers trap platelets into microthrombi and red cells shear into schistocytes. The pentad is Fever, microangiopathic hemolytic Anemia, Thrombocytopenia, Renal dysfunction, and Neurologic changes such as confusion. PT and PTT stay normal. Plasma exchange removes the inhibitor and replaces ADAMTS13.

Do NOT transfuse platelets in TTP: new platelets fuel more microthrombi.

Hemolytic uremic syndrome (HUS). Classic HUS follows bloody diarrhea in children from Shiga toxin–producing E. coli O157:H7. The toxin injures glomerular endothelium, producing the triad of microangiopathic hemolytic anemia (schistocytes), thrombocytopenia, and acute kidney injury. Neurologic signs are less prominent than in TTP; care is supportive, with dialysis if needed.

Disseminated intravascular coagulation (DIC). Widespread activation of coagulation consumes platelets and factors while secondary fibrinolysis runs, so patients bleed and clot at once. Triggers: Sepsis, Trauma, Obstetric complications (placental abruption, amniotic fluid embolism), acute Pancreatitis, Malignancy (especially acute promyelocytic leukemia), and snakebite. Labs: LOW platelets, HIGH PT and PTT, LOW fibrinogen, HIGH D-dimer, and schistocytes. Treat the trigger and replace platelets, plasma, or cryoprecipitate for active bleeding.

Heparin-induced thrombocytopenia (HIT). In type II HIT, IgG against heparin–platelet factor 4 (PF4) complexes activates platelets. The count drops more than 50% at days 5–10, and the danger is paradoxical arterial or venous THROMBOSIS, not bleeding. Risk is higher with unfractionated than low-molecular-weight heparin, and the serotonin release assay confirms the diagnosis. Stop all heparin and start a direct thrombin inhibitor such as argatroban; avoid warfarin acutely (skin necrosis risk) until platelets recover. Type I HIT is a mild, nonimmune dip in the first days of therapy.

Qualitative Platelet Disorders

Bernard-Soulier syndrome. An autosomal recessive defect in GpIb blocks platelet ADHESION to vWF. Platelets are BIG and reduced in number, and the ristocetin assay is abnormal, as in vWD; unlike vWD, adding normal plasma does not correct it. Mnemonic: Bernard-Soulier = Big platelets, GpIb.

Glanzmann thrombasthenia. An autosomal recessive defect in GpIIb/IIIa prevents fibrinogen bridging, so AGGREGATION fails. The count is normal, but platelets show no clumping on the smear; the ristocetin response is normal.

Uremia. Renal failure poisons platelet function, causing a QUALITATIVE defect of adhesion and aggregation with a normal count and a prolonged bleeding time. Correct the uremia with dialysis and give DDAVP (desmopressin), which releases vWF from endothelium, for acute bleeding.

Antiplatelet drugs. Aspirin irreversibly blocks COX-1 and thromboxane A₂ for the life of the platelet; abciximab and eptifibatide block GpIIb/IIIa, mimicking Glanzmann.

Coagulation Factor Disorders

von Willebrand disease (vWD). The MOST common inherited bleeding disorder, usually autosomal dominant. Low vWF impairs platelet adhesion (mucocutaneous bleeding, prolonged bleeding time) AND lowers factor VIII, which vWF normally stabilizes, so the PTT can be prolonged. The ristocetin cofactor assay is abnormal. DDAVP releases stored vWF and treats most cases.

Hemophilia A and B. X-linked recessive deficiency of factor VIII (hemophilia A, more common) or factor IX (hemophilia B, Christmas disease) causes deep bleeds and hemarthroses in boys. The PTT is HIGH with a normal PT, platelet count, and bleeding time. A mixing study corrects the PTT unless an inhibitor (anti-factor antibody) is present. Treatment is factor replacement.

Vitamin K deficiency. Vitamin K, regenerated by epoxide reductase, is the cofactor for γ-carboxylation of factors II, VII, IX, and X and proteins C and S; warfarin inhibits epoxide reductase. Deficiency occurs in newborns (sterile gut), with broad-spectrum antibiotics, and with fat malabsorption. The PT prolongs first because factor VII is shortest-lived, then the PTT. Newborns receive IM vitamin K at birth to prevent hemorrhagic disease of the newborn.

Thrombophilias

Factor V Leiden. The MOST common inherited hypercoagulable state (~5% of Caucasians). A point mutation makes factor V resistant to cleavage by activated protein C (APC resistance), so it stays active and promotes clotting. It presents as venous thromboembolism (DVT, PE), sometimes recurrent or at a young age.

• Prothrombin G20210A: raises prothrombin levels; the second most common inherited thrombophilia.
• Antithrombin deficiency: heparin acts through antithrombin, so it produces a reduced or absent rise in PTT; also acquired through urinary loss in nephrotic syndrome.
• Protein C or S deficiency: warfarin drops short-lived protein C first, creating a transient hypercoagulable start and a risk of warfarin-induced skin necrosis.
• Hyperhomocysteinemia: from B12, folate, or B6 deficiency; predisposes to thrombosis.
• Antiphospholipid syndrome (acquired): lupus anticoagulant prolongs the PTT in vitro yet causes thrombosis and pregnancy loss.