Section 12.2: Coagulation and Bleeding Disorders (ITP, TTP, Hemophilia, vWD)

PANCE Blueprint & Clinical Significance

Coagulation and bleeding disorders are tested heavily on the PANCE, particularly the clinical and laboratory differences between platelet disorders (primary hemostasis defects) and clotting factor deficiencies (secondary hemostasis defects). Candidates must be able to recognize emergency presentations like Thrombotic Thrombocytopenic Purpura (TTP), identify specific factor deficiencies, and select appropriate treatments.

Primary vs. Secondary Hemostasis

To answer PANCE questions correctly, you must first classify the bleeding disorder as primary or secondary hemostasis. Primary hemostasis involves platelet plug formation. Defects in primary hemostasis (e.g., ITP, TTP, vWD) present with mucocutaneous bleeding (petechiae, purpura, epistaxis, gingival bleeding, menorrhagia) and immediate bleeding after injury. Secondary hemostasis involves the coagulation cascade to form a fibrin clot. Defects in secondary hemostasis (e.g., Hemophilia A/B) present with deep tissue and joint bleeding (hemarthrosis, hematomas) and delayed bleeding after trauma.

Immune Thrombocytopenic Purpura (ITP)

Pathophysiology

ITP is an autoimmune disorder characterized by the production of anti-platelet autoantibodies (typically IgG) directed against platelet membrane glycoproteins (such as GPIIb/IIIa). These antibody-coated platelets are subsequently recognized and cleared prematurely by splenic macrophages, leading to severe thrombocytopenia. Platelet production in the bone marrow may also be impaired.

Clinical Presentation

Patients present with signs of primary hemostatic dysfunction: petechiae, purpura, epistaxis, gingival bleeding, and menorrhagia. Crucially, there is no splenomegaly, hepatomegaly, or lymphadenopathy on physical examination (the presence of these findings should prompt consideration of leukemia or lymphoma). ITP has a bimodal distribution: in children, it typically presents as an acute, self-limiting disease following a viral infection; in adults, it is usually chronic and insidious.

Diagnostic Workup

ITP is a diagnosis of exclusion. Laboratory findings show isolated thrombocytopenia (platelet count often < 50,000, and sometimes < 10,000). The white blood cell count, hemoglobin, and coagulation studies (PT and aPTT) are normal. A bone marrow biopsy is not routinely required but will show normal to increased megakaryocytes (platelet precursors).

Clinical Management

In children, observation is the primary strategy unless significant mucosal bleeding is present, as most cases resolve spontaneously. In adults, treatment is indicated if the platelet count is < 30,000 or if there is active bleeding. First-line therapies include systemic corticosteroids (e.g., prednisone or dexamethasone) to decrease antibody production and splenic clearance, intravenous immunoglobulin (IVIG) to saturate splenic Fc receptors, or anti-D immunoglobulin (in Rh-positive, non-splenectomized patients). Second-line therapies for refractory or chronic cases include thrombopoietin receptor agonists (romiplostim, eltrombopag), rituximab, or splenectomy.

Thrombotic Thrombocytopenic Purpura (TTP)

Pathophysiology

TTP is a life-threatening microangiopathic hemolytic anemia (MAHA) resulting from a severe deficiency of the metalloproteinase ADAMTS13. This enzyme is responsible for cleaving ultra-large von Willebrand factor (vWF) multimers. In the absence of functional ADAMTS13 (usually due to an acquired autoantibody), these ultra-large multimers persist, binding to platelets and creating microthrombi in the microvasculature. This leads to mechanical shearing of red blood cells (hemolysis) and systemic platelet consumption (thrombocytopenia).

Clinical Presentation

The classic presentation of TTP is defined by the FAT RN pentad:

• Fever: systemic inflammatory response.
• Anemia: microangiopathic hemolytic anemia causing pallor, jaundice, and fatigue.
• Thrombocytopenia: leading to petechiae and purpura.
• Renal insufficiency: hematuria, proteinuria, and elevated creatinine.
• Neurological symptoms: fluctuating confusion, headache, focal deficits, seizures, or coma.

Crucially, patients rarely present with all five components; the dyad of MAHA (schistocytes on smear) and unexplained thrombocytopenia is sufficient to suspect TTP and initiate emergency treatment.

Diagnostics

Peripheral blood smear is the key initial test, revealing prominent schistocytes (helmet cells, fragmented RBCs). Laboratory findings show severe thrombocytopenia, elevated lactate dehydrogenase (LDH) and indirect bilirubin (indicative of hemolysis), and low haptoglobin. Coagulation studies (PT and aPTT) are normal, which is a vital differentiator from Disseminated Intravascular Coagulation (DIC). An ADAMTS13 activity level < 10% confirms the diagnosis.

Management

TTP is a medical emergency with a high mortality rate (> 90%) if left untreated. Immediate treatment is plasma exchange (plasmapheresis, PEX), which removes the autoantibodies and replenishes functional ADAMTS13. Corticosteroids and rituximab are initiated concurrently to suppress autoantibody production. PANCE Trap: Platelet transfusions are strictly contraindicated in TTP (unless there is life-threatening hemorrhage) because transfusing platelets will fuel the microvascular thrombotic process and worsen organ ischemia.

Hemophilia A and B

Pathophysiology

Hemophilia A and B are X-linked recessive congenital bleeding disorders. Hemophilia A is caused by a deficiency of clotting Factor VIII, whereas Hemophilia B (Christmas disease) is caused by a deficiency of clotting Factor IX. Both factors are part of the intrinsic pathway of the coagulation cascade.

Clinical Presentation

Unlike platelet disorders, hemophilias present with signs of secondary hemostatic dysfunction: spontaneous hemarthrosis (bleeding into joints, classically the knees, elbows, and ankles), deep tissue hematomas, and delayed, prolonged bleeding after minor trauma or surgery. Bleeding is typically delayed because the initial platelet plug forms normally, but the fibrin mesh stabilizes it poorly. Petechiae and purpura are absent.

Diagnostics

Coagulation studies reveal a prolonged activated partial thromboplastin time (aPTT) with a normal prothrombin time (PT), normal platelet count, and normal bleeding time. A mixing study is performed: mixing the patient's plasma with normal plasma will correct the prolonged aPTT, indicating a factor deficiency rather than an inhibitor. Specific factor assays (measuring Factor VIII or IX activity) provide the definitive diagnosis.

Management

Acute bleeding episodes and surgical prophylaxis are managed with prompt factor replacement therapy (recombinant Factor VIII for Hemophilia A; recombinant Factor IX for Hemophilia B). In patients with mild Hemophilia A, desmopressin (DDAVP) can be administered because it stimulates the release of endogenous Factor VIII and vWF from endothelial cells. DDAVP is ineffective in Hemophilia B. Patients should avoid aspirin and NSAIDs.

von Willebrand Disease (vWD)

Pathophysiology

vWD is the most common inherited bleeding disorder, typically inherited in an autosomal dominant fashion. von Willebrand factor (vWF) has two critical roles: it acts as an adhesive bridge between platelet glycoprotein Ib (GPIb) and subendothelial collagen during vascular injury (primary hemostasis), and it serves as a carrier protein that stabilizes clotting Factor VIII in circulation (preventing its rapid degradation).

Clinical Presentation

Patients typically present with mild-to-moderate mucocutaneous bleeding: easy bruising, recurrent epistaxis, gingival bleeding, and significant menorrhagia. Bleeding may also be noted after dental extractions or minor surgical procedures.

Diagnostics

Coagulation studies show a normal platelet count. The aPTT may be normal or prolonged (depending on the degree of Factor VIII reduction, as vWF stabilizes Factor VIII). The bleeding time (though historically used) is prolonged. Screening and diagnosis require a triad of tests: vWF antigen level (quantitatively reduced in Type 1), ristocetin cofactor activity assay (measures vWF-mediated platelet agglutination; reduced in vWD), and Factor VIII activity level.

Management

Treatment depends on the type and severity. For Type 1 vWD (the most common type, representing a quantitative deficiency), desmopressin (DDAVP) is the treatment of choice for minor bleeding or preoperative prophylaxis. For patients with Type 2 (qualitative defect) or Type 3 (severe, complete absence), or during major surgery/hemorrhage, vWF-containing factor concentrates (such as Humate-P) are administered. Avoidance of antiplatelet medications is mandatory.

Coagulation Profiles of Bleeding Disorders