Disorders of Hemostasis in Critically Ill Patients

Jeremiah Boles

Alice D. MA

Disorders of hemostasis are common in critically ill patients. This chapter will review hemostasis, pathophysiology of commonly encountered congenital and acquired bleeding disorders along with their associated symptoms, laboratory findings, and management.

Review of Normal Hemostasis

Hemostasis can be broken into a series of steps occurring in overlapping sequence. Primary hemostasis refers to the interactions between the platelet and the injured vessel wall, culminating in the formation of a platelet plug. The humoral phase of clotting, or secondary hemostasis, encompasses a series of enzymatic reactions, resulting in a hemostatic fibrin plug. Finally, fibrinolysis and wound repair occur. Each of these steps is carefully regulated, and perturbations can predispose to either hemorrhage or thrombosis. Depending on the nature of the defect, the hemorrhagic or thrombotic tendency can be either profound or subtle.

Primary hemostasis begins at the site of vascular injury, with platelets adhering to the subendothelium, utilizing interactions between molecules such as collagen and von Willebrand factor (vWF) in the vessel wall with glycoprotein (GP) receptors on the platelet surface. Upon exposure to agonists present at a wounded vessel, signal transduction leads to platelet activation. Via a process known as inside-out signaling, the platelet membrane integrin α_2bβ₃ (also known as GP IIbIIIa) undergoes a conformational change to be able to bind fibrinogen, which cross-links adjacent platelets, leading to platelet aggregation. Secretion of granular contents is also triggered by outside signals, potentiating further platelet activation (Fig. 108.1). Lastly, the surface of the platelet changes to serve as an adequate scaffold for the series of biochemical reactions resulting in thrombin generation.

Following platelet activation, a series of enzymatic reactions take place on phospholipid surfaces, culminating in the formation of a stable fibrin clot. Several models have attempted to make sense of these reactions. The cascade model was developed by two groups nearly simultaneously [1,2] and explained the extrinsic, intrinsic, and common pathways leading to fibrin formation (Fig. 108.2). While the cascade model accounts for the physiologic reactions underlying the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), it fails to explain completely the bleeding diathesis seen in individuals deficient in factors XI, IX, and VIII, as well as the lack of bleeding in those deficient only in contact factors. A cell-based model of hemostasis has been developed to address these deficiencies. In this model, upon vascular injury, the membrane of a tissue factor (TF)-bearing cell such as an activated monocyte or fibroblast serves as a platform for generation of a small amount of thrombin and FIXa, which then serves to activate platelets and cleave FVIII from vWF. Newly formed FVIIIa participates in the tenase complex on the surface of activated platelets to form FXa that interacts with the FVa generated on the platelet surface to form the prothrombinase complex. This complex generates a large burst of thrombin which is sufficient to cleave fibrinogen, activate FXIII, and activate the thrombin activatable fibrinolysis inhibitor (TAFI), thus allowing for formation of a stable fibrin clot (Fig. 108.2).

Fibrinolysis leads to clot dissolution once wound healing has occurred, in order to restore normal blood flow. Plasminogen is activated to plasmin by the action of either tissue plasminogen activator (t-PA) or urokinase plasminogen activator (u-PA). Plasmin degrades fibrin and fibrinogen and can thus dissolve both formed clot as well as its soluble precursor. Plasmin is inhibited by a number of inhibitors, of which α₂-plasmin inhibitor is the most significant. Plasminogen activation is also inhibited by a number of molecules; chief among them is plasminogen activator inhibitor-1 (PAI-1). Lastly, cellular receptors act to localize and potentiate or clear plasmin and plasminogen activators (see Chapter 111 for further discussion).

Approach to the Bleeding Patient

Physicians in the intensive care unit (ICU) often encounter bleeding patients and it can be difficult to identify which of these patients require further evaluation. Patients who experience bleeding that is excessive, spontaneous, or delayed following surgery or tissue injury require further investigation, which must begin with a thorough clinical history. A bleeding history should assess a patient’s exposure and response to all hemostatic challenges in the past such as trauma, surgery, and childbirth. Characterization of menses in females also may be revealing. Several bleeding assessment tools have been developed and are useful in the evaluation for an underlying coagulopathy, particularly von Willebrand disease (vWD) [3]. This history should also identify coexisting medical conditions such as liver, kidney, or thyroid disorders. A careful medication history is also important, including use of all over-the-counter medications which may contain aspirin, as well as any herbal preparations. Also of cardinal importance is an evaluation for a family history of abnormal bleeding. An inherited or congenital bleeding disorder is suggested by abnormal bleeding with onset shortly after birth and persistence throughout life. It is further supported by a family history with a consistent genetic pattern. However, it is important to note that a negative family history does not exclude a congenital bleeding disorder. For instance, approximately one third of all cases of hemophilia A arise from spontaneous mutations. Many of the rare coagulation disorders, including deficiency of factors II, V, VII, X,
as well as vWD type 2 N, among others, are inherited in an autosomal recessive fashion, and the parents of the patient may be entirely asymptomatic.

Figure 108.1. Primary hemostasis. (1) Exposure of subendothelium at sites of vascular disruption results in platelet adhesion via GPIb and GP VI with exposed von Willebrand factor (vWF) and collagen, respectively. Following platelet adhesion TxA₂ is produced and released which promotes vasoconstriction and platelet aggregation. (2) Platelet adhesion also results in fusion of cytoplasmic granules to the plasma membrane. Release of alpha and dense granules activates nearby platelets. (3) Platelet activation results in exposure of GPIIb/IIIa on the platelet surface allowing fibrinogen to cross bridge platelets resulting in a platelet plug.

A bleeding history should also ascertain past sites/mechanisms of bleeding. Surgical bleeding in patients with an underlying hemorrhagic condition is typically described as “diffuse oozing,” without the readily identifiable bleeding source seen with a surgical mishap such as a severed vessel. Patients with platelet disorders typically manifest mucocutaneous bleeding such as gingival bleeding and epistaxis as well as menorrhagia, petechiae, and ecchymoses. Platelet defects impact primary hemostasis and therefore the bleeding in these disorders is often immediate following surgery or trauma, whereas delayed bleeding is more classically associated with coagulation disorders. Patients with coagulation defects typically present with hemorrhages into soft tissues such as muscles and joints.

A physical examination should pay particular attention to the skin, joints, mucosal surfaces, and liver and spleen size.

Laboratory Assays of Primary and Secondary Hemostasis

While the history and physical examination can increase suspicion for the presence of a bleeding disorder, laboratory confirmation is required for precise diagnosis and treatment.
Laboratory evaluation is particularly crucial in individuals who are suspected of having a bleeding disorder but in whom prior bleeding is absent, such as those with mild congenital bleeding disorders who never previously underwent a sufficient hemostatic challenge, or those with acquired hemorrhagic disorders.

Figure 108.2. Secondary hemostasis. A: Tissue factor (TF) pathway cascade model of coagulation—basis for prothrombin time (PT) laboratory assay. B: Circulating FVIIa binds TF on a TF-bearing cell. TF/FVIIa along with calcium (Ca) and phospholipid (lipid) form the “extrinsic tenase” complex and converts FX to FXa. FXa combines with FVa, calcium, and phospholipid, “prothrombinase” complex, to activate FII to FIIa which in turn converts fibrinogen into fibrin. C: Contact activation pathway model of coagulation—basis for partial thromboplastin time (PTT) laboratory assay. D: On an activated platelet surface, FXIa activates FIXa. FIXa is also formed on the surface of a TF-bearing cell (B). FIXa, along with FVIIIa, Ca, and lipid, constitute the “intrinsic tenase” complex. This complex converts FX to FXa with subsequent FIIIa generation through the prothrombinase complex. (Courtesy of Dougald Monroe.)

Initial Evaluation of Primary Hemostasis—Platelet Function

An assessment of a patient’s platelet count is fundamental in evaluating primary hemostasis. This is typically part of a complete blood count (CBC). Reduced platelet counts, or thrombocytopenia, may be seen in a large number of acquired and congenital conditions. Evaluation and management of thrombocytopenia is further discussed in Chapter 109.

An evaluation of the peripheral smear is also cardinal in any evaluation of a bleeding patient. It allows one to assess platelet size and morphology, presence of platelet clumping (pseudothrombocytopenia), leukocyte inclusions, and red cell fragments, among other aberrancies, which may further direct workup and treatment.

Traditionally, platelet function was evaluated by bleeding time (BT). However, many institutions have discontinued using this test given the difficulty in standardization. Furthermore, the BT has been shown to be an inadequate predictor of bleeding, particularly in preoperative risk assessment [4]. More recently, automated tests have been developed to assess platelet function. The most widely used is the platelet function analyzer (PFA-100®). This assay measures the time required (closure time) for flowing whole, citrated blood to occlude an aperture in a membrane impregnated with a combination of either collagen and epinephrine or collagen and adenosine diphosphate (ADP). Closure time is affected by platelet count, hematocrit, platelet function, and vWF [5]. The PFA-100® appears to assess platelet function with greater sensitivity and reproducibility than the BT; however, a recent position statement from the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Hemostasis noted that although the PFA-100® is abnormal in some platelet disorders, it was not felt to have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders [6].

Evaluation of Secondary Hemostasis—Coagulation

The PT and the aPTT are assays performed on citrated plasma, which require enzymatic generation of thrombin on a phospholipid surface. Prolongation of the PT and the aPTT can be seen in individuals with either deficiencies of, or inhibitors to, humoral clotting factors, though not all patients with prolongations of these assays will have bleeding diatheses (Table 108.1).

The PT measures the time needed for formation of an insoluble fibrin clot once citrated plasma has been recalcified and thromboplastin has been added, indicating activity of factors VII, V, X, and II and fibrinogen. It commonly is used to monitor anticoagulation with vitamin K antagonists such as warfarin. Since thromboplastin from various sources and different lots can affect the rates of clotting reactions, the International Normalized Ratio (INR) measurement was developed
to avoid some of this variability in PT measurement. Each batch of thromboplastin reagent has assigned to it a numerical International Sensitivity Index (ISI) value, which is used in the formula:

Table 108.1 Laboratory Test Abnormalities in Common Acquired and Congenital Bleeding Disorders

	Acquired bleeding disorders	Congenital bleeding disorders
PT elevated, aPTT wnl	Liver disease DIC Vitamin K deficiency Vitamin K antagonists (e.g., warfarin)	FVII deficiency
PT wnl, aPTT elevated	Heparin Lupus inhibitor Acquired FVIII inhibitor	Hemophilia A and B FXI deficiency Severe vWD
Both PT and aPTT elevated	Heparin overdose Warfarin overdose FVI inhibitors FX inhibitors Severe DIC Severe vitamin K deficiency Severe liver disease Direct thrombin inhibitors	Afibrinogenemia Hypo- or dysfibrino-genemia Prothrombin deficiency FV deficiency Combined deficiency of FV and FVIII
Both PT and aPTT wnl	LMWH therapy Fondaparinux therapy Antiplatelet agents Acquired vWD Scurvy Acquired thrombocytopenia	vWD FXIII deficiency Congenital platelet dysfunction Congenital thrombocytopenia Collagen disorders (e.g., Ehlers–Danlos syndrome)
wnl, within normal limits; DIC, disseminated intravascular coagulation; LMWH, low-molecular-weight heparin; PT, prothrombin time; PTT; partial thromboplastin time; vWD, von Willebrand disease.

The INR is less predictive of bleeding in patients with liver disease, and can be inaccurate in patients with lupus anticoagulants that are strong enough to affect the PT.

The aPTT tests the activity of factors XII, XI, IX, VIII, X, V, and II, and fibrinogen, high-molecular-weight kininogen (HMWK), and plasma prekallikrein (PK) [7]. Citrated plasma is recalcified, and phospholipids (to provide a scaffold for the clotting reactions) and an activator of the intrinsic system such as kaolin, celite, or silica are added. The reagents used show variable sensitivities to inhibitors such as lupus anticoagulants and heparin, and to deficiencies (if any) in involved clotting factors, and normal ranges will vary from laboratory to laboratory. aPTT values that are vastly different from one laboratory to another should prompt suspicion of a lupus anticoagulant.

The Thrombin Clotting Time and Reptilase Time

The thrombin clotting time (TCT) or thrombin time (TT) measures the time needed for clot formation once thrombin is added to citrated plasma. Thrombin enzymatically cleaves fibrinopeptides A and B from the α– and β-chains of fibrinogen, allowing for polymerization into fibrin. The TT is prolonged in the presence of any thrombin inhibitor such as heparin, lepirudin, or argatroban; by low levels of fibrinogen or structurally abnormal fibrinogen (dysfibrinogens); and by elevated levels of fibrinogen or fibrin degradation products, which can serve as nonspecific inhibitors of the reaction. Patients with paraproteins can have a prolonged TT because of the inhibitory effect of the paraprotein on fibrin polymerization.

Reptilase is snake venom from Bothrops atrox which also enzymatically cleaves fibrinogen. Reptilase cleaves only fibrinopeptide A from the α-chain of fibrinogen, but fibrin polymerization still occurs. Reptilase time (RT) is not affected by heparin but may be more sensitive than the TT to the presence of a dysfibrinogenemia.

Mixing Studies

Mixing studies are used to evaluate prolongations of the aPTT (less commonly the PT or the TT) and are useful in making the distinction between an inhibitor and a clotting factor deficiency. The patient’s plasma is mixed 1:1 with normal control plasma, and the assay is repeated (with or without prolonged incubation at 37°C). Correction of the clotting test signifies factor deficiency, since the normal plasma will supply the deficient factor. Incomplete correction of the clotting test after mixing suggests the presence of an inhibitor, since an inhibitor will prolong clotting in normal plasma. Incomplete correction can sometimes be seen with nonspecific inhibitors such as lupus anticoagulants, elevated fibrin split products, or a paraprotein. Less commonly, deficiencies of multiple clotting factors can lead to incomplete correction of the mixing study, since the mixing study was designed to correct deficiency of a single factor.

Tests of specific factor activity levels as well as evaluation for vWD will be discussed in the following sections.

Congenital Disorders of Hemostasis

Due to a requirement for specialized management, all cases of suspected or proven congenital hemostatic defects require consultation with a hematologist upon admission to the critical care setting.

Von Willebrand Disease

It has been estimated that lower-than-reference levels of vWF occur in 1% of the population worldwide and therefore vWD is the most common congenital bleeding disorder [8]. However, only a fraction of the aforementioned individuals are symptomatic (approximately 5% of those with low levels) [9]. vWD is inherited in an autosomal manner with the more common type I disease being autosomal dominant.

vWD constitutes a quantitative or qualitative deficiency in vWF, and is divided into three subtypes according to the pathophysiology. Types 1 and 3 are the result of a partial (type 1) or virtually a complete (type 3) quantitative deficiency of vWF, while type 2 is a qualitative defect in vWF. Type 1 vWD represents the most common subtype accounting for approximately 70% of patients, while type 2 accounts for 15% to 20% and type 3 for only 2% to 5% of vWD patients [10].

Because bleeding symptoms in persons with vWD may be absent or overlooked until a major hemorrhage due to surgery or trauma has occurred, the diagnosis should be considered in an ICU patient with otherwise unexplained excessive bleeding, particularly if there is a significant family history including an autosomal pattern of inheritance. The most common historical bleeding symptoms include epistaxis, increased bleeding after dental extractions, and menorrhagia. A validated bleeding assessment tool has been developed to screen outpatients who may benefit from formal vWD laboratory testing [3], but its usefulness in the critical care setting has not been established.

A formal diagnosis of vWD should be based on three components: (a) a history of excessive bleeding, either spontaneous mucocutaneous and/or postsurgical, (b) a positive family history for excessive bleeding, and (c) confirmatory laboratory testing. Diagnostic tests for vWD, reviewed elsewhere [11], should be performed in a specialized laboratory and are summarized in Table 108.2.

The goals of treatment in vWD are to correct the quantitative or qualitative deficiencies in vWF, platelets, and FVIII. Treatment options include desmopressin (DDAVP), vWF-containing concentrates, and/or antifibrinolytics. See Tables 108.3 and 108.4 for general treatment guidelines.

In normal volunteers, DDAVP increases plasma levels of FVIII, vWF, and tissue plasminogen activator [12]. It may be given IV or SQ [13]. When given intravenously, the FVIII and vWF levels are usually increased three- to fivefold above basal levels within 30 minutes. vWD patients should undergo a DDAVP trial to gauge their individual response since there is considerable interindividual variability. Dosing of DDAVP for vWD is generally recommended at 0.3 μg per kg (IV or SQ), or 300 μg intranasally, which can be repeated at intervals of 12 to 24 hours. Tachyphylaxis (due to depletion of FVIII/vWF from repeated endothelial exocytosis into plasma) following repeated dosing is expected; DDAVP given as a second dose is 30% less effective than the first dose [14]. For this reason, and due to the risk of hyponatremia (which can lead to seizures), serial dosing should be limited to two to three doses in a 72-hour period with concurrent free water restriction and monitoring of serum sodium levels. DDAVP is most effective in type 1 vWD. It is relatively contraindicated in type 2B vWD because of the transient induction of thrombocytopenia [15]. Patients
with type 3 vWD are usually unresponsive to DDAVP. Certain hemophilia treatment centers caution against use of DDAVP in patients with coronary artery disease, since this agent may also activate platelets.

Table 108.2 Expected Laboratory Values in Vwd from the Nhlbi

Antifibrinolytic agents (epsilon aminocaproic acid and tranexamic acid) can be used alone or as adjunctive treatment in vWD patients with mucosal bleeding. These drugs inhibit fibrinolysis by inhibiting plasminogen activation, thereby promoting clot stability. They are contraindicated in the setting of gross hematuria as resultant ureteral obstruction by insoluble clot has been described. Given a concern for thrombosis, antifibrinolytics should be avoided in patients with
prothrombotic conditions, disseminated intravascular coagulation (DIC), or when receiving prothrombin complex concentrates (PCCs).

Table 108.3 Dosing Guidelines for Von Willebrand Disease (VWD) Treatment

Medication	Dose	Comments
DDAVP	Nasal spray: 300 μg (1 spray in each nostril) If weight < 50 kg 150 μg (1 spray in 1 nostril) IV: 0.3 μg/kg (not to exceed 20–25 μg)	Most useful in type 1 vWD, ineffective in type 3. Requires challenge to document efficacy. Relatively contraindicated in type 2B as may exacerbate thrombocytopenia May repeat dose in 12 h and/or 24 h. Tachyphylaxis occurs with repeat dosing. Due to risk of hyponatremia, if dosing serially, limit doses to no more than 2–3 in a 72-h period, fluid restrict, and follow serum sodium levels. Avoid in patients with coronary disease.
Antifibrinolytic agents: epsilon-aminocaproic acid (EACA) Tranexamic acid	50 mg/kg PO up to q 6h (lower doses may be effective) or 1 g/h IV continuous infusion Do not exceed 24 g/24 h 25 mg/kg q 8 h (not yet available in the United States)	Especially useful for mucocutaneous bleeding, especially for dental procedures May be used as adjunctive treatment (DDAVP, factor concentrates) Avoid in upper urinary tract bleeding
vWF-containing FVIII concentrates (e.g., Humate-P, Alphanate)	60–80 RCoF U/kg as an initial dose, then 40–60 u/kg IV every 12 h (see Table 108.4)	FVIII activity levels are often used in the monitoring of response to vWF-containing products as real-time vWF activity measures are not always available Dosed in RCoF units. Individual product is labeled with ratio of RCoF units:FVIII
DDAVP, desmopressin; vWD, von Willebrand disease; vWF, von Willebrand factor; RCoF, ristocetin cofactor.

Table 108.4 Suggested Initial Dosing of VWF Concentrates for Prevention or Management of Bleeding

	Major surgery/bleeding
Loading dose^a	60–80 RCoF U/kg
Maintenance dose	40–60 RCoF U/kg, typically every 12 h initially
Monitoring	vWF:RCo and FVIII trough and peak, at least daily
Therapeutic goal	Trough vWF:RCo and FVIII > 50 IU/dL for 7–14 d
Safety parameter	Do not exceed vWF:RCo 200 IU/dL or FVIII 250–300 IU/dL
May alternate with DDAVP for latter part of treatment
	Minor surgery/bleeding
Loading dose^a	30–60 U/kg
Maintenance dose	20–40 U/kg every 12–48 h
Monitoring	vWF:RCo and FVIII trough and peak, at least once
Therapeutic goal	Trough vWF:RCo and FVIII > 50 IU/dL for 3–5 d
Safety parameter	Do not exceed vWF:RCo 200 IU/dL or FVIII 250–300 IU/dL
May alternate with DDAVP for latter part of treatment
^aLoading dose is in vWF:RCo IU/dL. Adapted from The National Heart, Lung, and Blood Institute. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, MD: National Institutes of Health Publication 08-5832, 2008.

vWF factor-containing FVIII concentrates are appropriate for patients with severe vWD or in situations when other therapies (including DDAVP) are ineffective and are preferred to cryoprecipitate, which contains vWF, but has not undergone viral inactivation. When used in the treatment of vWD, they are dosed in ristocetin cofactor (RCoF) units, as opposed to FVIII units (Table 108.4). Limited data suggest a role for rFVIIa in patients with type 3 vWD who have developed alloantibodies to vWF [16].

The National Heart Lung and Blood Institute has recently published guidelines for the diagnosis, evaluation, and management of vWD [17].

Hemophilia

The hemophilias are congenital bleeding disorders characterized by X-linked inheritance and result in a deficiency of FVIII (hemophilia A) or FIX (hemophilia B). In the United States, they have a combined incidence of 1 in 5,000 male births. Hemophilia A is more common than hemophilia B and accounts for approximately 80% of cases. Since hemophilia is an X-linked disorder, all daughters of affected males are obligate carriers and all sons are healthy. Females may rarely manifest bleeding symptoms if they (a) are the homozygous offspring from a carrier mother and affected father, (b) have a high degree of lyonization, or (c) are a carrier with concomitant Turner’s syndrome (XO).

The clinical phenotype of hemophilia patients depends on the residual level of circulating procoagulant protein (FVIII or FIX). It is possible to differentiate three degrees of clinical severity: (a) mild hemophilia (5% to 50% factor activity) in which bleeding is prolonged but typically only occurs following trauma or surgery, (b) moderate hemophilia (1% to 5% factor activity) in which prolonged bleeding follows minor trauma, and (c) severe hemophilia (< 1% factor activity) where patients experience spontaneous hemorrhage into joints (hemarthrosis) and muscles.

In severe and moderate hemophilia, the PT is normal and the aPTT is prolonged. However, the PTT may be normal in patients with mild hemophilia whose residual factor activity is > 20%. If the aPTT is prolonged, it should correct with a mixing study, since hemophilia is a factor deficiency syndrome. Specific factor assays should be performed to confirm a diagnosis of hemophilia A or B.

The management of most cases of hemophilia, thanks to the availability of replacement clotting factor concentrates, occurs in the outpatient setting, but individuals who previously have escaped diagnosis (mild or moderate hemophilia) or who have sustained major trauma or complications from a bleeding episode (compartment syndrome) may present to critical care. If not previously diagnosed, hemophilia should be suspected in male patients who have a personal history of bleeding into joints or muscles, a history of excessive bleeding upon surgical challenge, and/or a positive sex-linked family history of bleeding.

Hemarthrosis, a hallmark of hemophilia, accounts for approximately 85% of all bleeding events in severe hemophilia and most commonly involves the ankles, knees, and elbows [18]. Intramuscular hematomas in persons with hemophilia may expand to the point where blood flow is compromised to surrounding neurovascular structures resulting in tissue gangrene and compartment syndrome; the condition requires surgery and aggressive clotting factor replacement therapy [19] (Table 108.5). Gastrointestinal bleeding is uncommon in hemophilia. However, patients with an underlying structural lesion may present with hematemesis, hematochezia, or melena. Hemophilia patients who present with evidence for gastrointestinal bleeding should have a complete endoscopic evaluation to assess for and treat any underlying lesion. Approximately 90% of persons with severe hemophilia will develop hematuria during their life, although the condition is typically painless, benign, and unassociated with a structural lesion. As discussed earlier, antifibrinolytic agents are contraindicated in patients with genitourinary bleeding.

Table 108.5 Recommended Hemostatic Levels in Hemophilia^a

Clinical situation	Hemophilia target factor activity (%)^a
Mild hemorrhage (joint, muscle)	30–40
Mucosal hemorrhage (oral, dental)	30–40 with EACA
Major hemorrhage	> 50
Life-threatening hemorrhage or perioperative management (major and orthopedic procedures)	100
^aMinimum recommended goal factor activity levels. EACA, epsilon-aminocaproic acid.

Hemorrhage into head and neck structures is a medical emergency in persons with hemophilia. Retropharyngeal hematoma, which may occur spontaneously or following dental or surgical procedures, may present with inability to control saliva, neck swelling, and pain. If untreated, it may result in airway compromise and in some cases may require tracheostomy. Hemorrhage into the central nervous system is a severe and potentially fatal (albeit rare) complication of hemophilia. Intracranial hemorrhage (ICH) may occur spontaneously in severe hemophilia or as the result of trauma. Prompt recognition of ICH is paramount and factor replacement therapy should be given immediately while the diagnostic workup is underway (Table 108.5).

The approach to treating major bleeding episodes in hemophilia A and B is similar. The clinical scenario dictates the target factor activity level (Table 108.5). For example, an ICH requires a target activity level of 100% initially, while levels of 30% to 40% may be sufficient for minor bleeds such as uncomplicated hemarthrosis. Prior to completion of the diagnostic (radiologic or otherwise) workup, clotting factor concentrate should be administered immediately to a person with hemophilia and a suspected life- or limb threatening bleed. Plasma-derived and recombinant factor concentrates [20] contain much higher concentrations of the desired factor compared to fresh frozen plasma (FFP) or cryoprecipitate. If possible, avoidance of FFP or cryoprecipitate is advised to avoid volume overload, transfusion-related lung injury (TRALI), and potential viral transmission (see Chapter 114).

DDAVP may be used instead of factor concentrate in selected patients with mild hemophilia A who have minor bleeding or a requirement for an enhanced FVIII activity level prior to a short-lived bleeding challenge. Any mild hemophilia A patient should undergo a DDAVP trial to gauge his or her individual response in lieu of assuming efficacy of the agent. FVIII levels in plasma increase two- to six-fold following administration. For mild hemophilia A, the recommended dose is 0.3 μg per kg (IV or SQ) or 300 μg intranasally; as previously discussed, tachyphylaxis and hyponatremia may develop after serial dosing.

Antifibrinolytic agents are a useful adjunctive treatment in hemophilia patients with mucosal bleeding. However, hemophilic patients with hematuria, DIC, receiving a PCC, or other prothrombotic conditions should not be treated with antifibrinolytics.

One of the most significant complications of hemophilia treatment is the development of an inhibitor. Inhibitors are alloantibodies against exogenously administered clotting factor that neutralize the factor. The development of a new inhibitor is more common in hemophilia A than in hemophilia B [21], in severe hemophilia, and among previously untreated patients (as opposed to adults who typically have been extensively exposed to clotting factor concentrate).

Inhibitors, if present at high titer, neutralize exogenous factor rendering factor concentrates ineffective. Therefore, an inhibitor should be suspected when administration of factor concentrate at a dose previously sufficient to achieve hemostasis, or improve bleeding, fails to do so. Once suspected, a Bethesda assay should be performed to document the titer of the inhibitor (reported in Bethesda units, BU). Of the two goals of treatment in patients with inhibitors, namely, to achieve adequate hemostasis and to eradicate the inhibitor, only the former is typically relevant to the critical care setting. Bleeding should be treated with bypassing agents, typically an activated prothrombin complex concentrate (aPCC) or rFVIIa [22]. If the titer is < 5 BU, high doses of FVIII or FIX may be given as initial treatment in cases of life- or limb-threatening bleeding episodes. In patients with a long-standing inhibitor, however, the anamnestic response negates factor activity after 5 to 7 days, at which point bypassing agents become necessary.

Rare Congenital Coagulation Disorders

Less Common Coagulation Factor Deficiencies

The hemophilias and vWD represent approximately 85% of congenital bleeding disorders. The remaining disorders will be briefly discussed next.

Disorders of Fibrinogen

Congenital fibrinogen disorders result from a quantitative (afibrinogenemia) or qualitative (dysfibrinogenemia) defect in fibrinogen synthesis. Congenital afibrinogenemia has a variable bleeding phenotype with the majority of patients experiencing moderate bleeding [23]. Afflicted individuals present typically in the neonatal period with umbilical stump bleeding or bleeding following circumcision [23]. Patients may also experience hemarthrosis, intramuscular hemorrhage, spontaneous abortion, mucosal surface bleeds, ICH, or spontaneous splenic rupture [24]. Heterozygotes are typically asymptomatic. The clinical phenotype in patients with congenital dysfibrinogenemia is variable and includes (a) asymptomatic (55%), (b) hemorrhagic (25%), (c) thrombotic (10% to 20%), or (d) a combination of both hemorrhagic and thrombotic complications (1% to 2%) [25]. Treatment of congenital fibrinogen disorders should be individualized given the clinical variability. In general, replacement therapy in the form of fibrinogen concentrates, cryoprecipitate, or (not recommended) FFP should be given to patients with a hemorrhagic presentation to achieve a goal fibrinogen level of 50 to 100 mg per dL [26].

Prothrombin (FII) Deficiency

Congenital prothrombin deficiency is characterized by a concordant decrease in prothrombin antigen and activity [27]. Aprothrombinemia has not been reported. Patients with hypoprothrombinemia present with severe hemorrhage including ICH, mucocutaneous bleeding, hemarthrosis, spontaneous abortions, and significant postoperative bleeding. Heterozygotes are usually asymptomatic; however, they may experience
increased postoperative bleeding [28]. Prothrombin deficiency is treated with factor replacement in the form of FFP or PCC to a goal prothrombin level of 30% [29].

Factor V Deficiency

FV deficiency is associated with mucocutaneous bleeding and rarely with ICH [30]. There are mild, moderate, and severe deficiency states. Patients with severe deficiency usually present with umbilical stump and mucocutaneous bleeding. Older individuals may present with postoperative bleeding or menorrhagia. FV deficiency is treated with FFP to a goal activity level of 20% to 30%. Alpha granules in platelets contain FV and platelet transfusions have been used in the treatment of FV deficiency when patients have developed neutralizing inhibitors to FV with varying success [31]. Combined deficiency of FV and FVIII should always be considered in the differential diagnosis of patients who present with FV deficiency. This is discussed next [32].

Combined Factor V and VIII Deficiency

Combined FV and FVIII deficiency (F5F8D) is a rare disorder where patients have detectable, but low antigen and activity levels of both factors, typically in the 5% to 15% range. Patients present with increased bleeding following trauma or surgery. Patients are treated with a combination of FFP and FVIII concentrates.

Factor VII Deficiency

Patients with less than 1% FVII activity manifest a severe bleeding disorder, predominantly involving the mucous membranes, muscles, joints, and following surgery or trauma, while those with more than 5% have relatively mild symptoms. Factor VII activity correlates poorly with bleeding severity, but in general, only modest amounts of circulating FVII are required for adequate hemostasis, and bleeding is uncommon, even with surgery, in individuals with FVII activity levels > 15% to 20% [33,34]. In the United States, rFVIIa is used to treat FVII deficiency. Plasma-derived FVII concentrates are available in Europe to treat this disorder [35,36]. When rFVIIa and/or FVII concentrates are unavailable, PCC (depending on factor formulation) or FFP may be used.

Factor X Deficiency

In congenital FX deficiency, severity of bleeding appears to correlate with residual FX activity and may be quite severe. In a case series of Iranian patients with congenital FX deficiency, the most common symptoms were epistaxis, menorrhagia, and hemarthrosis [37]. FX deficiency is treated with PCCs.

Factor XI Deficiency

FXI deficiency, previously known as hemophilia C, is common amongst Ashkenazi Jews where the gene frequency is 8% to 9% [38]. The inheritance is autosomal rather than X linked as with hemophilia A and B. Severe FXI deficiency (< 15% to 20% FXI activity) occurs in homozygotes or compound heterozygotes. Heterozygous individuals have a partial FXI deficiency (20% to 70% FXI activity) [39]. Bleeding is unpredictable as some severe FXI deficiency patients are asymptomatic, while an analysis of 50 kindreds demonstrated that 30% to 50% of heterozygotes experienced significant bleeding [40].

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