Hematologic Conditions

Hemophilia

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Definition and Epidemiology

Hemophilia A and B are X-linked recessive inherited bleeding disorders affecting 1:5000 males with no racial predilection.1–3 Hemophilia A is caused by deficiency of factor VIII and hemophilia B is caused by deficiency of factor IX. The normal plasma levels of factor VIII or factor IX range between 50% and 150%. The severity of hemophilia is predictive of risk for bleeding and is based on plasma levels of the factor VIII or IX (Table 16-1).1

Table 16-1. Severity of Hemophilia

Severity	Plasma Level of Factor VIII or IX
Mild	More than 5%
Moderate	Between 1% and 5%
Severe	Less than 1%

Pathogenesis

Hemophilias are X-linked inherited bleeding disorders resulting from deficiency of clotting factors VIII or IX. Two examples of how hemophilia can be inherited are illustrated in Figures 16-1 and 16-2.2 Female carriers have adequate levels of clotting factors because of the one normal X chromosome and do not manifest the clinical disease. In a very rare circumstance, a girl may be born with hemophilia when her father has hemophilia and the mother is a carrier. Hemophilia can also occur in males who are not born to mothers who are not carriers of the abnormal gene because of mutation in the gene.

Figure 16-1

Mode of inheritance of hemophilia. The mother is a carrier of hemophilia. Each daughter has a 50% chance of inheriting the abnormal gene from her mother and being a carrier. Each son has a 50% chance of inheriting the abnormal gene from his mother and having hemophilia. (From:www.nhlbi.nih.gov.)

Figure 16-2

Mode of inheritance of hemophilia. The father has hemophilia. The mother is not a carrier of hemophilia. Each daughter will inherit the abnormal gene from her father and be a carrier. None of the sons will inherit the abnormal gene from their father, and, therefore, none will have hemophilia. (From:www.nhlbi.nih.gov.)

Clinical Presentation

Clinically hemophilia A and B are indistinguishable and the differentiation is based on factor assays. The clinical presentation depends upon the severity of the hemophilia. Patients with hemophilia may present with a history of easy bruising, spontaneous bleeding in the joints or muscles, and prolonged bleeding after trauma1–3 They are also at risk for intracranial bleeding and internal bleeding at various other sites such as gastrointestinal tract and kidneys. Hemophilia should be differentiated from the most common inherited bleeding disorder, von Willebrand disease resulting from von Willebrand factor abnormality. The characteristics and differences between hemophilias and von Willebrand disease are summarized in Table 16-2.1

Table 16-2. Characteristics and Differences between Hemophilias and von Willebrand’s Disease

	Hemophilia A	Hemophilia B	von Willebrand’s Disease
Incidence	1:5,000	1:30,000	1%–3% of US population
Abnormality	Factor (F) VIII deficiency. Normal levels: 50%–150%	F IX deficiency	VWF abnormality
		Normal levels: 50%–150%
Inheritance	X-linked, affects males	X-linked, affects males	Autosomal dominant (gene on chromosome 12).
	Gene at the tip of X-chromosome		Affects males and females
Site of production	Unknown	Liver, vitamin K depended protein	Megakaryocytes and endothelial cells
Function of protein	Cofactor; forms “tenase” complex with FIX and activate FX	Clotting protein (zym ogen). Activated by F XI or VIIa and forms a “tenase” complex with FVIII and activates FX	Platelet adhesion, protection of F VIII
Classification (Normal plasma levels of FIII and IX = 50–150%)	Mild (>5%) Moderate (1%–5%) Severe (<1%)	Mild (>5%)	Types 1
		Moderate (1%–5%)	Type 2 (2A, 2B, 2M, 2N)
		Severe (<1%)	Type 3
Clinical manifestations	Positive family history (30% new mutation).	Positive family history (30% new mutation).	Positive family history
	Hemarthroses, hematomas, intracranial hemorrhages, hematuria, gastrointestinal hemorrhage, and so forth	Milder disease, though identical hemorrhage sites as hemophilia A	Mucocutaneous (epistaxis, menorrhagia, postdental bleeding). Type 3 may present as hemophilia A
PFA/Bleeding time	Normal	Normal	May be prolonged
PT	Normal	Normal	Normal
APTT	Prolonged	Prolonged	Prolonged or normal
F VIII assay	Decreased or absent	Normal	↓ or Normal
F IX assay	Normal	Decreased or absent	Normal
VWF: antigen	Normal	Normal	Decreased or absent (type 3)
VWF R: Co	Normal	Normal	Decreased or abnormal
VWF multimers	Normal	Normal	Normal or abnormal
Specific treatment	Recombinant (r) F VIII (preferred), virally safe plasma derived concentrates	Recombinant F IX, virally safe plasma derived concentrates	DDAVP (intranasal or intravenous) VWF concentrates (plasma derived)
Inhibitor patients	rFVIIa, FEIBA	rFVIIa	Rare
Adjunct treatment	Antifibrinolytics	Antifibrinolytics	Oral contraceptives, antifibrinolytics

Diagnosis

Diagnosis is suspected based on positive family history and clinical presentation and confirmed by factor assays. An approach to laboratory diagnosis to a bleeding patient is presented in Figure 16-3.

Figure 16-3

Evaluation of bleeding patient. Screening tests assess the degree of hemorrhage and the adequacy of hemostasis in a bleeding patient. (Used with permission from Kulkarni R, Gera R, Scott-Emuakpor AB. Adolescent hematology. In: Greydanus DE, Patel DR, Pratt HD, eds. Essential Adolescent Medicine. New York: McGraw Hill; 2006:371-390.)

Treatment

Patients should be managed in consultation with a hematologist at hemophilia treatment centers (Box 16-1). Treatment is directed at raising and maintaining the factor levels above which the risk of bleeding is minimized.1,2,4–6 For minor bleeding such as joint or muscles the factor level should be raised up to 30% and for major bleeding such as internal organ bleeding it should be raised up to 100%. The factor level is raised by intravenous administration (either bolus or continuous infusion) of specific factor (factor VIII or IX or von Willebrand) concentrate. One unit per kilogram of body weight will raise plasma factor VIII by 2%, factor IX by 1.5%, and von Willebrand facor (Ristocetin cofactor activity) by 1.5%.1,4 The typical dose for prophylactic regimen for factor VIII is 25 to 40 U/kg body weight every other day and for factor IX is 25 to 40 U/kg body weight two times per week.

Box 16-1 When to Refer

When to Consult Hematologist

Bleeding disorders

Sickle cell disease and other hemoglobinopathies

Thrombotic disorders and thrombophilia

Thrombocytopenias

Severe iron deficiency anemia with complications

Chronic anemia not responding to treatment

Hemolytic anemias

Aplastic anemias

Desmopressin has been shown to effectively raise the plasma levels of factor VIII and von Willebrand factor by two- to sixfold and is used to treat mild hemophilia A and von Willebrand disease.1,4 Epsilon amino caproic acid or tranexamic acid are used as adjunct hemostatic therapy for mucosal bleeds.

Sports participation and regular exercise are encouraged for patients with hemophilias and von Willebrand disease.1,2,5,6 Sport participation and regular physical activity have been shown to have significant positive effect on joint health, overall health, and psychosocial well being. Category 1 sports such as swimming, golf, and running are considered safe to allow full participation; category 2 sports such as bowling, weight lifting, and biking in which the benefits outweigh the risks are also generally appropriate to allow participation; and category 3 sports such as football and skateboarding in which the risks outweigh the potential benefits are generally not considered safe to allow participation. Athletes should maintain their factor levels in the normal range and administration of factor concentrate before the anticipated physical activity is also recommended. Factors to be considered in planning athletic participation include preparticipation evaluation and clearance by hematologist, ready availability of appropriate factor concentrate, knowledge by the athlete and the staff involved of the location and contact information of nearest hemophilia center while traveling for away games, and specific emergency action plan in case of bleeding.5 Specific sport related issues are summarized in Table 16-3.

Table 16-3. Canadian Hemophilia Society Guidelines for Sport Participation

Sport	Risk of Sport	Joints Involved (Ranked in Descending Order of Involvement)	Degree of Stress to Joints	Recommended Equipment	Additional Comments
Swimming	Very low	Shoulders	+	None	Swimming is a low-risk sport assuming no diving is involved.
					Stress to joints is directly related to intensity and duration of swimming.
					Whipkick may irritate knees.
Waterskiing	High	Knees	+++	Life jacket	Very stressful on muscles.
		Shoulders	++
		Elbows	++		The overall risk is high because of outside forces over which skier has no control (examples: speed at which he hits the water, being hit by a ski).
Windsurfing	Medium	Spine	++	Life jacket	Lessons useful initially to learn proper technique. High winds increase risk especially if inexperienced.
		Shoulders	++
		Elbows	+
Golf	Low	Shoulders	+	Appropriate footwear
		Elbows	+
		Knees	+
Tennis	Low	Knees	++	Tennis shoes
		Ankles	++
		Elbows	+
Squash/Racquetball	Medium	Knees	+++	Appropriate footwear	Protective eyeglasses. Contact with ball, racquet could be harmful.
		Ankles	+++
		Elbows	++
		Shoulders	++
Volleyball	Low/medium	Knees	++	Knee pads	Increased risk with higher level of competition.
		Hands (fingers/wrists)	++	High-top running shoes
		Ankles	+
Basketball	Low/medium	Knees	+++	High-top running shoes	High-top running shoes may prevent ankle sprains. Knee pads provide some form of cushioning when falling on knees.
		Ankles	+++
		Fingers	++	Knee pads
Baseball	Medium	Shoulders	++	Knee pads	Higher risk of soft tissue injuries
		Knees	++	Appropriate footwear
		Elbows	++
		Ankles	++	Helmet (batting)
Soccer	Medium	Ankles	+++	Appropriate footwear	Higher risk of soft tissue injuries
		Knees	++
		Hips	++	Shin pads
Football (tackle)	High	Knees	+++	Helmet	High risk of head injuries and traumatic bleeds because of repeated heavy physical contact in tackle football.
		Ankles	+++	Protective pads
		Shoulders	+++
Rugby	High	Knees	+++	Generally not used in this sport	Harmful because of high risk of physical contact.
		Ankles	+++
		Shoulders	+++
					Increased risk of head injury and jarring injury to the spine.
Weight lifting	Medium	Elbows	+++		Proper lifting techniques can lessen risk of injury.
		Shoulders	+++
		Back	+++
					Recommended lifting through mid-range only. Increase number of repetitions rather than weight. Train regularly. Not recommended for young children.
Skating	Low	Knees	++	Proper fitting skates with good ankle support.	Helmet is advisable during initial learning period. Knee pads or snow pants.
		Ankles	++
Skateboarding	High	Knees	+++	Helmet	Risk of fracture and head injury owing to falling.
		Ankles	+++	Knee and elbow pads
Roller skating/roller blading	High	Spine	Stress on joints related to falling.	Helmet	Risk of injury is high owing to risk of falling on hard surfaces. Rough surfaces, hills, and ramps increase risk.
				Knee, elbow and shin pads
Road hockey	Medium	Knees	++	Helmet and knee pads may be beneficial.	Contact with stick and other players could be harmful.
		Ankles	++
Ice hockey	High	Knees	+++	Proper fitting skates with good ankle support.	Contact with puck, stick, boards, other players could be harmful.
		Shoulders	+++
		Ankles	++
				Protective padding (shoulder, elbows, knees).
				Helmet
Nordic skiing (cross-country)	Low/medium	Knees	++	Skis and poles of appropriate length.	The difficulty of the course will directly affect the degree of stress on joints and overall risk such as risk of falling.
		Ankles	++
		Shoulders	+
				Boots with good support.
Alpine skiing (downhill)	High	Knees	+++	Helmet	Appropriate length of skis and poles. The risk of head injury is high owing to the inherent risk of falling at high speeds.
				Ski boots
Horseback riding	High	Spine	++	Helmet	The risk of head injury and serious muscle or joint injury is high owing to the possibility of falling off or being thrown from the horse. Jumping should be avoided.
Bicycling	Low	Knees	+	Properly adjusted bike with seat at proper height.	To minimize stress on knees: Keep seat high. Avoid hills. Stay in lower gears. Pedal at high revolution (80–100/min).
				Bicycle helmet.
				Toe straps.
Running	Low/medium	Ankles	++	Appropriate footwear (need good shock absorption, firm heel-counter, arch support).	Running surface (e.g., concrete or uneven ground) will affect risk. Intensity of running (such as distance, speed, frequency) will also affect risk.
		Knees
Karate/Judo	Medium/high	Knees	++		None. If there is contact, the risk of injury is high. Without contact, the training can be good for improving muscle flexibility, coordination and balance.
		Elbow	++
		Ankles	+