Coagulation Disorders¶
Chapter 121 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Hemophilia A and B are X-linked recessive disorders caused by FVIII and FIX deficiencies, respectively, with hemophilia A being more common (1 in 5000 males).
- Disseminated intravascular coagulation (DIC) is characterized by microvascular thrombosis and consumptive coagulopathy, with key features including prolonged PT, aPTT, and elevated D-dimer.
- Vitamin K deficiency impairs synthesis of clotting factors II, VII, IX, X, and proteins C/S, leading to prolonged PT and aPTT, with treatment requiring vitamin K or plasma-derived products.
- Acquired inhibitors to coagulation factors (e.g., FVIII) are immune-mediated and require immune suppression, bypass agents (e.g., recombinant FVIIa), or emicizumab for management.
- Gene therapy and recombinant factor concentrates have revolutionized hemophilia treatment, enabling prophylaxis and reducing inhibitor formation.
1. DEFINITION & OVERVIEW¶
Coagulation disorders encompass inherited and acquired defects in hemostasis, including deficiencies of clotting factors, inhibitors, and abnormalities in fibrin formation. These disorders range from mild to severe, with clinical manifestations from spontaneous bleeding to life-threatening hemorrhage or thrombosis.
Table 121-1: Genetic and Laboratory Characteristics of Inherited Coagulation Disorders¶
| CLOTTING FACTOR DEFICIENCY | INHERITANC E | PREVALENC E IN GENERAL P OPULATION | LABORATO RY ABNORM ALITYa | MINIMUM HE MOSTATIC LEVELS | TREATMENT | PLASMA HALF-LIFE |
|---|---|---|---|---|---|---|
| Fibrinogen | AR | 1 in 1,000,000 | + | 100 mg/dL | Cryoprecipitat e | 2–4 d |
| Prothrombin | AR | 1 in 2,000,000 | + | 20–30% | FFP/PCC | 3–4 d |
| Factor V | AR | 1 in 1,000,000 | +/- | 15–20% | FFPc | 36 h |
| Factor VII | AR | 1 in 500,000 | - | 15–20% | FFP/PCC | 4–6 h |
| Factor VIII | X-linked | 1 in 5000 | + | 30% | FVIII concentrates | 8–12 h |
| Factor IX | X-linked | 1 in 30,000 | + | 30% | FIX concentrates | 18–24 h |
| Factor X | AR | 1 in 1,000,000 | +/- | 15–20% | FFP/PCC | 40–60 h |
| Factor XI | AR | 1 in 1,000,000 | + | 15–20% | FFP | 40–70 h |
| Factor XII | AR | ND | + | b | b | 60 h |
| HK | AR | ND | + | b | b | 150 h |
| CLOTTING FACTOR DEFICIENCY | INHERITANC E | PREVALENC E IN GENERAL P OPULATION | LABORATO RY ABNORM ALITYa | MINIMUM HE MOSTATIC LEVELS | TREATMENT | PLASMA HALF-LIFE |
|---|---|---|---|---|---|---|
| Prekallikrein | AR | ND | + | b | b | 35 h |
| Factor XIII | AR | 1 in 2,000,000 | - | 2%–5% | Cryoprecipitat e/FXIII concentrates | 11–14 d |
1.1 Inherited vs. Acquired Disorders¶
Inherited disorders (e.g., hemophilia, von Willebrand disease) result from genetic mutations, while acquired disorders (e.g., DIC, vitamin K deficiency, inhibitors) arise from environmental, drug-induced, or systemic factors. Inherited disorders often present in childhood, while acquired disorders may develop secondary to trauma, infection, or malignancy.
1.2 Coagulation Cascade Overview¶
The coagulation cascade involves intrinsic (contact activation), extrinsic (tissue factor), and common pathways. Key factors include FVII, FX, and thrombin, with fibrin formation mediated by FXIII. Laboratory tests (PT, aPTT, TT) assess pathway function.
2. EPIDEMIOLOGY¶
Inherited coagulation disorders affect ~1 in 10,000 males globally, with hemophilia A (80% of cases) and B (20%) being most common. Acquired disorders like DIC are more prevalent, often secondary to sepsis, trauma, or malignancy. Vitamin K deficiency is rare in adults but common in newborns without prophylaxis.
2.1 Risk Factors¶
Genetic mutations (e.g., F8/F9), liver disease, malnutrition, anticoagulant use (e.g., warfarin), and infections (e.g., HIV, HCV) increase risk. Severe liver disease and malabsorption syndromes predispose to vitamin K deficiency.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Inherited deficiencies (e.g., hemophilia, von Willebrand disease) result from genetic mutations. Acquired causes include DIC (microvascular thrombosis), vitamin K deficiency, inhibitors, and liver disease. Pathophysiology involves impaired clotting factor synthesis, consumption, or functional defects.
Table 121-2: Common Clinical Causes of Disseminated Intravascular Coagulation¶
| SEPSIS | IMMUN OLOGIC DISORD ERS | TRAUM A AND TISSUE INJURY | DRUGS | VASCU LAR DIS ORDER S | ENVEN OMATIO N | OBSTE TRICAL COMPLI CATION S | LIVER D ISEASE | CANCE R | MISCEL LANEO US |
|---|---|---|---|---|---|---|---|---|---|
| Bacterial (Staphyl ococci, s treptoco cci, pneu mococci, meningo cocci, gr am-nega tive bacilli) | Acute he molytic tr ansfusio n reaction | Brain injury (g unshot), extensiv e burns, fat embo lism, rha bdomyol ysis | Fibrinoly tic agents, aprotinin , warfarin, prothrom bin complex concentr ates, rec reational drugs (a mpheta mines) | Giant he mangio mas (Ka sabach- Merritt s yndrome ), large vessel a neurysm s | Snake, insect | Abruptio placenta e, amniotic fluid em bolism, dead fetus syn drome, septic abortion | Fulmina nt hepatic failure, cirrhosis, fatty liver of pregn ancy | Adenoca rcinoma (prostate , pancre as, etc.), hematol ogic mali gnancies (acute pr omyeloc ytic leuk emia) | Shock, r espirator y distress syndrom e, massive transfusi on |
3.1 Hemophilia Pathogenesis¶
X-linked recessive mutations in F8 (hemophilia A) or F9 (hemophilia B) lead to deficient clotting activity. Inhibitors (autoantibodies) may develop, neutralizing factor activity and complicating treatment.
3.2 DIC Mechanisms¶
Systemic activation of coagulation by sepsis, trauma, or malignancy leads to microvascular thrombosis and consumption of clotting factors. Fibrinolytic activation results in secondary bleeding and disseminated intravascular coagulation.
4. CLINICAL FEATURES¶
Symptoms vary by disorder: hemarthrosis in hemophilia, petechiae/ecchymoses in DIC, and mucosal bleeding in vitamin K deficiency. Severe cases may present with life-threatening hemorrhage, organ failure, or thrombosis.
4.1 Hemophilia Manifestations¶
Joint bleeds (hemarthrosis), soft tissue hematomas, and muscle bleeds. Severe cases may develop chronic arthropathy, synovitis, and progressive joint deformity.
4.2 DIC Presentation¶
Petechiae, purpura, ecchymoses, and bleeding from GI, respiratory, or CNS. Organ failure (e.g., ARDS, renal failure) and thrombosis (e.g., pulmonary embolism) may occur.
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish between inherited disorders (e.g., hemophilia, von Willebrand disease), acquired inhibitors, and other conditions like liver disease or malignancy. Laboratory tests (PT, aPTT, mixing studies) help differentiate.
5.1 Hemophilia vs. von Willebrand Disease¶
Hemophilia presents with joint bleeds; von Willebrand disease has mucosal bleeding. Factor VIII activity is reduced in hemophilia, while von Willebrand factor (VWF) and FVIII levels are abnormal in VWD.
6. INVESTIGATIONS & DIAGNOSIS¶
Laboratory tests include PT, aPTT, TT, fibrinogen, and factor assays. Mixing studies and Bethesda assays detect inhibitors. Imaging (e.g., ultrasound for hemarthrosis) and clinical context guide diagnosis.
Table 121-3: ISTH Criteria for Overt DIC¶
| PARAMETER | VALUE | POINTS |
|---|---|---|
| Platelets | >100,000 × 10n/L | 0 |
| Platelets | >50–<100 × 10n/L | 1 |
| Platelets | <50 × 10n/L | 2 |
| d-Dimer | Normal | 0 |
| d-Dimer | Moderate increase | 2 |
| d-Dimer | Severe increase | 3 |
| Prothrombin time (PT) | <3 s | 0 |
| Prothrombin time (PT) | 3–<6 s | 1 |
| Prothrombin time (PT) | >6 s | 2 |
| Fibrinogen | >1 g/L | 0 |
| Fibrinogen | <1 g/L | 1 |
| Total Score | <5 | Low-grade DIC |
| Total Score | >5 | Overt DIC |
6.1 Diagnostic Algorithms¶
- Initial screening: PT and aPTT. 2. Mixing study to identify factor deficiency vs. inhibitor. 3. Factor assays (e.g., FVIII, FIX) and inhibitor titration (Bethesda assay). 4. D-dimer for DIC.
7. MANAGEMENT & TREATMENT¶
Factor replacement (e.g., FVIII, FIX concentrates), antifibrinolytics (e.g., aminocaproic acid), and bypass agents (e.g., recombinant FVIIa) are mainstays. Immune suppression (e.g., rituximab) and gene therapy are used for inhibitors or severe cases.
7.1 Hemophilia Treatment¶
Factor replacement (3–5% of body weight for FVIII/FIX), prophylaxis (weekly infusions), and emicizumab for inhibitors. Avoid antiplatelet drugs and manage bleeding with PCC or recombinant FVIIa.
7.2 DIC Management¶
Address underlying cause (e.g., sepsis, trauma). Supportive care with platelets, FFP, and anticoagulants (e.g., heparin). Avoid excessive transfusion in non-bleeding patients.
8. PROGNOSIS & COMPLICATIONS¶
Severe hemophilia without treatment may lead to joint deformity, chronic pain, and reduced life expectancy. DIC is associated with high mortality (30–80%) due to organ failure. Vitamin K deficiency can cause neonatal hemorrhage if untreated.
8.1 Long-Term Outcomes¶
Prophylaxis improves quality of life and reduces joint damage. Gene therapy offers long-term correction of factor deficiencies. DIC survivors may have residual organ dysfunction.
9. SPECIAL CONSIDERATIONS¶
Pregnancy requires careful factor management to prevent postpartum hemorrhage. Neonatal vitamin K prophylaxis prevents hemorrhagic disease. Liver disease patients may require plasma-derived products for coagulation support.
9.1 Pregnancy and Hemophilia¶
Factor levels increase during pregnancy; infusion to 50–70% for 3–5 days post-delivery prevents postpartum hemorrhage. DDAVP may be used for mild cases.
10. KEY POINTS & CLINICAL PEARLS¶
- Use mixing studies to differentiate factor deficiency from inhibitors.
- Emicizumab is effective for FVIII inhibitors.
- Prophylaxis reduces joint damage in hemophilia.
- DIC requires urgent management of underlying causes.
- Vitamin K deficiency is preventable with neonatal prophylaxis.