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Coagulation Disorders¶

Part 4: Oncology and Hematology · Part 4 – Hematologic Disorders & Hemostasis · Part 4 – Hematologic Disorders & Hemostasis · Chapter 121

Key Clinical Points¶

Isolated prolonged PT suggests FVII deficiency; prolonged aPTT indicates intrinsic factors (FVIII, FIX, FXI) or lupus anticoagulant.
Mixing studies differentiate factor deficiencies (corrects with plasma) from inhibitors/anticoagulants (does not correct).
Hemophilia A (FVIII deficiency) is the most common hemophilia (80%); severe disease is <1% factor activity.
DDAVP (0.3 μg/kg) increases FVIII levels 2–3x in mild/moderate Hemophilia A but is ineffective in severe cases.
High-titer inhibitors (>5 BU) in Hemophilia A require bypass agents like aPCC or rFVIIa.
DIC involves uncontrolled thrombin generation, consumption of factors/platelets, and secondary fibrinolysis leading to organ failure.
FXI deficiency causes prolonged aPTT but lacks a bleeding phenotype due to redundant pathways.
Vitamin K deficiency affects factors II, VII, IX, X, and proteins C and S; Warfarin inhibits VKORC1.
Emicizumab is a bispecific antibody bridging FIXa and FX to bypass FVIII in Hemophilia A.
Liver disease presents a 'double-edged sword' of pro-thrombotic (high FVIII/VWF, low Protein C/S) and bleeding risks.

DEFINITION & CLASSIFICATION¶

Coagulation disorders involve inherited or acquired deficiencies of clotting factors leading to bleeding diathesis.

• Genetic Deficiencies: e.g., Hemophilia A/B; cause lifelong recurrent bleeding into joints and muscles. • Acquired Disorders: Include liver disease, DIC, and vitamin K deficiency. • Inhibitors: Antibodies to clotting factors that complicate management in hemophilia patients. • Prothrombin Complex Concentrates (PCCs): Used for factor replacement and warfarin reversal.

Laboratory Assessment of Coagulation¶

Initial screening tests include PT, aPTT, and TT:

• Isolated prolonged PT: Indicates FVII deficiency. • Prolonged aPTT: Indicates intrinsic pathway factors (FVIII, FIX, FXI) or lupus anticoagulant. • Both PT/aPTT prolonged: Suggests FV, FX, FII, or fibrinogen abnormalities.

Mixing Study Logic:

• Corrects with normal plasma → Factor deficiency. • Does not correct → Inhibitor or anticoagulant present.

Additional Testing:

• Individual factor assays.

• Bethesda assay: Quantifies inhibitor titer (1 BU = 50% neutralization of FVIII/FIX in 2 h).

EPIDEMIOLOGY¶

Global prevalence and inheritance patterns:

• Hemophilia A: 80% of hemophilia cases; 1 in 10,000 males worldwide. • Hemophilia B: 20% of cases; X-linked recessive. • FXI Deficiency: 1 in 1,000,000 in general population; higher prevalence in Ashkenazi and Iraqi Jewish populations (6% heterozygotes; 0.1–0.3% homozygotes).

Note: De novo mutations account for ~30% of hemophilia cases with no family history.

Hemophilia Prevalence¶

• Hemophilia A: 80% of all cases. • Hemophilia B: 20% of cases. • Incidence: 1 in 10,000 males globally. • Female Carriers: May have asymptomatic or mild bleeding due to lyonization.

FXI Deficiency Prevalence¶

• General Population: 1 in 1,000,000. • Specific Populations: High prevalence in Ashkenazi and Iraqi Jewish populations (6% heterozygotes; 0.1–0.3% homozygotes).

• Genetic Diversity: >65 mutations identified in FXI gene.

ETIOLOGY & PATHOPHYSIOLOGY¶

Mechanisms of coagulopathy:

• Hemophilia: X-linked mutations in F8 (A) or F9 (B) genes. • DIC: Uncontrolled thrombin generation from tissue factor activation, endothelial damage, and fibrinolysis. • Vitamin K Cycle: γ-glutamylcarboxylase carboxylates clotting factors; warfarin inhibits VKORC1.

Hemophilia Pathogenesis¶

• Hemophilia A: F8 gene mutations (e.g., intron 22 inversion in 40% of severe cases). • Hemophilia B: F9 gene mutations.

• Diagnostics: Molecular diagnostics enable carrier identification and precise mutation analysis.

DIC Pathophysiology¶

• Activation: Tissue factor release from damaged cells activates coagulation. • Amplification: Neutrophil extracellular traps (NETs) and polyphosphates amplify thrombin generation. • Systemic Impact: SIRS/cytokine storm worsens endothelial dysfunction and fibrinolysis.

• Purpura Fulminans: Severe DIC in children with protein C deficiency.

Vitamin K Cycle¶

• Mechanism: γ-Glutamylcarboxylase carboxylates glutamic acid residues on clotting factors. • Enzyme Role: VKORC1 regenerates reduced vitamin K. • Warfarin Action: Inhibits VKORC1, reducing activity of vitamin K-dependent factors (II, VII, IX, X) to 1–30% normal.

CLINICAL FEATURES¶

Symptoms and signs by disorder:

• Hemophilia: Recurrent hemarthroses (knees, elbows), joint deformity ('target joints'), muscle hematomas, and life-threatening bleeds. • FXI Deficiency: Mucocutaneous bleeding (bruises, epistaxis) after trauma; postoperative bleeding common. • DIC: Organ failure from microvascular thrombosis, systemic bleeding, and purpura fulminans.

Hemophilia Clinical Manifestations¶

• Joints: Recurrent hemarthroses in knees/hips → synovitis and joint destruction. • Chronic Damage: Leads to 'target joints' and surgical intervention. • Internal Bleeding: Retroperitoneal hemorrhage: Pseudotumor formation with femoral nerve damage.

• Mucosal Bleeds: Hematuria common; managed with antifibrinolytics.

FXI Deficiency Clinical Manifestations¶

• Spontaneous Bleeding: Rare. • Trauma-induced: Mucocutaneous bleeding (bruises, gum bleeding) common.

• Surgery: Postoperative bleeding occurs in 30–50% of patients despite low FXI levels.

DIC Clinical Manifestations¶

• Microvascular Thrombosis: Leads to organ failure (lung, kidney, brain).

• Consumption: Systemic bleeding from platelet/fibrinogen consumption.

• Purpura Fulminans: Skin necrosis with thrombosis in children.

DIFFERENTIAL DIAGNOSIS¶

Key diagnostic considerations based on lab profiles:

• Isolated prolonged PT → FVII deficiency.

• Prolonged aPTT → Hemophilia A/B, FXI deficiency, or lupus anticoagulant.

• Both PT/aPTT prolonged → FV, FX, FII, or fibrinogen deficiency.

Factor Deficiency DDx¶

• FVII deficiency: Isolated prolonged PT.

• Hemophilia A/B: Prolonged aPTT, normal PT.

• FXI deficiency: Prolonged aPTT, normal PT.

• FV/FX/FII/fibrinogen deficiency: Both PT/aPTT prolonged.

DIC DDx¶

• Etiologies: Sepsis, trauma, obstetric complications, cancer, immunologic disorders, drugs, vascular disease, envenomation, liver disease.

• ISTH Criteria: Score >5 (Table 121-3) indicates overt DIC.

DIAGNOSTIC APPROACH¶

Stepwise diagnostic evaluation:

Initial Screening: Perform PT, aPTT, and TT.
PT: Evaluates extrinsic pathway and common factors.
aPTT: Evaluates intrinsic pathway and common factors.
TT: Evaluates fibrinogen and inhibitors.
Mixing Study: Determine if correction occurs with normal plasma.
Corrects → Factor deficiency.
Does not correct → Inhibitor/anticoagulant.
Specific Assays:
Bethesda assay: Quantify inhibitor titer (1 BU = 50% neutralization of FVIII/FIX in 2 h).
DIC Scoring (Table 121-3):
Platelets <50 imes 10^9/L → 2 points.
d-Dimer severe increase → 3 points.
PT >6 s → 2 points.
Fibrinogen <1 g/L → 1 point.
Total Score >5 → Overt DIC.

Table 121-1: Genetic and Laboratory Characteristics of Inherited Coagulation Disorders¶

Key findings from Table 121-1:

• Fibrinogen: AR; PT+, aPTT+, TT+; Min level 100 mg/dL; Treatment: Cryoprecipitate.

• Prothrombin: AR; PT+, aPTT+, TT-; Min level 20–30%; Treatment: FFP/PCC.

• Factor VII: AR; PT+, aPTT-, TT-; Min level 15–20%; Treatment: FFP/PCC.

• Factors VIII, IX, XI: aPTT+; PT- (or +/-); TT-.

• Factor XII: aPTT+; PT-, TT-; No bleeding phenotype.

Table 121-3: ISTH Criteria for Overt DIC¶

Scoring system for overt DIC:

• Platelets <50 imes 10^9/L: 2 points.

• d-Dimer severe increase: 3 points.

• PT >6 s: 2 points.

• Fibrinogen <1 g/L: 1 point.

• Total Score >5: Overt DIC.

MANAGEMENT & TREATMENT¶

Treatment protocols by condition:

Hemophilia Management:
Prophylaxis: FVIII/FIX concentrates (target >1% activity).
DDAVP (0.3 μg/kg): Raise FVIII 2–3x in mild/moderate cases.
Bypass agents: aPCC or rFVIIa for high-titer inhibitors (>5 BU).
Emicizumab: Bispecific antibody for hemophilia A with/without inhibitors.
FXI Deficiency Management:
Major bleeds: FFP or PCCs.
Mucosal bleeding: Antifibrinolytics (tranexamic acid).
Note: No routine prophylaxis recommended.
DIC Management:
Primary action: Treat underlying cause (e.g., sepsis, trauma).
Transfusion support: Platelets/fibrinogen only for active bleeding or invasive procedures.
Contraindication: Anticoagulants (heparin) are contraindicated in overt DIC.

Table 121-2: Common Clinical Causes of DIC¶

Common triggers for DIC include:

• Sepsis: Bacterial, Viral, Mycotic, Parasitic, Rickettsial.

• Trauma/Injury: Brain injury, burns, fat embolism, rhabdomyolysis.

• Obstetrical: Abruptio placentae, amniotic fluid embolism, dead fetus syndrome.

• Other: Cancer, Venoms, Drugs (Warfarin in neonates), Liver disease.

COMPLICATIONS & PROGNOSIS¶

Clinical outcomes and risks:

• Hemophilia: - Severe cases: Joint destruction, inhibitor development (30% of patients). - Life expectancy: ~10 years shorter than general population. - Improvement: Gene therapy and emicizumab improve quality of life.

• DIC: - Mortality: 30–50% in sepsis-related DIC. - Organ failure: Resulting from microvascular thrombosis (lung, kidney, brain). - Bleeding: Resulting from secondary hyperfibrinolysis.

Table 121-4: Coagulation Disorders and Hemostasis in Liver Disease¶

Liver disease creates a complex balance:

• Pro-thrombotic factors: Reduced Protein C/S, increased FVIII, increased VWF.

• Bleeding risk factors: Decreased clotting factors (II, VII, IX, X), low platelets, and systemic fibrinolysis.

SPECIAL POPULATIONS¶

Specific considerations for unique patient groups:

• Pregnancy: - FVIII levels increase 2–3x in carriers. - Postpartum drop increases bleeding risk. - Prophylaxis: Factor concentrate (50–70%) for 3 days (vaginal) or 5 days (cesarean).

• Aging Patients: - Increased joint damage and inhibitor prevalence with age. - Emicizumab improves outcomes in elderly patients.

KEY PEARLS & HIGH-YIELD POINTS¶

Critical clinical insights:

• FXII Deficiency: Not a bleeding disorder despite prolonged aPTT due to redundant pathways.

• Emicizumab Monitoring: Requires chromogenic FVIII assay for monitoring.

• DIC Management: Avoid heparin in overt DIC; transfusion only for active bleeding.

• Vitamin K Impact: Vitamin K deficiency affects factors II, VII, IX, X, and proteins C and S.

• Diagnostic Clues: - Prolonged aPTT with normal PT → FVIII/FIX/FXI deficiency. - Mixing study correction → factor deficiency; no correction → inhibitor/anticoagulant.

Reference Tables¶

TABLE 121-1 Genetic and Laboratory Characteristics of Inherited Coagulation Disorders¶

Harrison's 22e, p.928

CLOTTING FACTOR DEFICIENCY	INHERITANCE	PREVALENCE IN GENERAL POPULATION	LABORATORY ABNORMALITYa			MINIMUM HEMOSTATIC LEVELS	TREATMENT	PLASMA HALF-LIFE
			aPTT	PT	TT
Fibrinogen	AR	1 in 1,000,000	+	+	+	100 mg/dL	Cryoprecipitate	2–4 d
	AR	1 in 2,000,000	+	+	−	20–30%	FFP/PCC
Factor V	AR	1 in 1,000,000	+/−	+/−	−	15–20%	FFPc	36 h
	AR	1 in 500,000	−	+	−	15–20%	FFP/PCC
Factor VIII	X-linked	1 in 5000	+	−	−	30%	FVIII concentrates	8–12 h
	X-linked	1 in 30,000	+	−	−	30%	FIX concentrates
Factor X	AR	1 in 1,000,000	+/−	+/−	−	15–20%	FFP/PCC	40–60 h
	AR	1 in 1,000,000	+	−	−	15–20%	FFP
Factor XII	AR	ND	+	−	−	b	b	60 h
	AR	ND	+	−	−	b	b
Prekallikrein	AR	ND	+	−	−	b	b	35 h
	AR	1 in 2,000,000	−	−	+/−	2%–5%	Cryoprecipitate/FXIII concentrates

TABLE 121-2 Common Clinical Causes of Disseminated Intravascular Coagulation SEPSIS • Bacterial:¶

Harrison's 22e, p.933

SEPSIS	IMMUNOLOGIC DISORDERS
• Bacterial: Staphylococci, streptococci, pneumococci, meningococci, gram-negative bacilli • Viral • Mycotic • Parasitic • Rickettsial	• Acute hemolytic transfusion reaction • Organ or tissue transplant rejection • Immunotherapy • Graft-versus-host disease
TRAUMA AND TISSUE INJURY	DRUGS
• Brain injury (gunshot) • Extensive burns • Fat embolism • Rhabdomyolysis	• Fibrinolytic agents • Aprotinin • Warfarin (especially in neonates with protein C deficiency) • Prothrombin complex concentrates • Recreational drugs (amphetamines)
VASCULAR DISORDERS	ENVENOMATION
• Giant hemangiomas (Kasabach- Merritt syndrome) • Large vessel aneurysms (e.g., aorta)	• Snake • Insects
OBSTETRICAL COMPLICATIONS	LIVER DISEASE
• Abruptio placentae • Amniotic fluid embolism • Dead fetus syndrome • Septic abortion	• Fulminant hepatic failure • Cirrhosis • Fatty liver of pregnancy
CANCER	MISCELLANEOUS
• Adenocarcinoma (prostate, pancreas, etc.) • Hematologic malignancies (acute promyelocytic leukemia)	• Shock • Respiratory distress syndrome • Massive transfusion

TABLE 121-3 International Society on Thrombosis and Haemostasis Criteria for Overt Disseminated Intravascular Congestion¶

Harrison's 22e, p.934

PARAMETER	VALUE	POINTS
Platelets	>100,000 × 109/L	0
	>50–<100 × 109/L	1
	<50 × 109/L	2
	Normal Moderate increase Severe increase
Prothrombin time (PT) prolonged	<3 s	0
	3–<6 s	1
	>6 s	2
	>1 g/L <1 g/L
Total Score		<5 Low-grade DIC >5 Overt DIC

TABLE 121-4 Coagulation Disorders and Hemostasis in Liver Disease Bleeding Portal hypertension Thrombocytopenia¶

Harrison's 22e, p.935

Bleeding
Portal hypertension
Esophageal varices
Thrombocytopenia
Splenomegaly
Chronic or acute DIC
Decreased synthesis of clotting factors
Hepatocyte failure
Vitamin K deficiency
Systemic fibrinolysis
DIC
Dysfibrinogenemia
Thrombosis
Decreased synthesis of coagulation inhibitors: protein C, protein S, antithrombin
Hepatocyte failure
Vitamin K deficiency (protein C, protein S)
Failure to clear activated coagulation proteins (DIC)
Dysfibrinogenemia